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= <big>Cell Cycle Withdrawal</big> =
= <big>Cell Cycle Withdrawal</big> =


'''Cell cycle withdrawal''' refers to the natural stoppage of [[cell cycle]] during [[cell division]].  This stoppage could be permanent or temporary, depending on the status of cells or the activities they are undergoing<ref>{{Cite journal|last=Yang|first=Lihui|last2=Baker|first2=Nicholas E.|date=2003|title=Cell cycle withdrawal, progression, and cell survival regulation by EGFR and its effectors in the differentiating Drosophila eye|url=https://www.ncbi.nlm.nih.gov/pubmed/12636917|journal=Developmental Cell|volume=4|issue=3|pages=359–369|issn=1534-5807|pmid=12636917}}</ref>. During the process, all cell duplication process, including [[mitosis]], [[meiosis]] as well as [[DNA replication]], will be paused<ref>{{Cite journal|last=Gooderham|first=Nigel J.|last2=Zhu|first2=Huijun|date=2006-05-01|title=Mechanisms of Induction of Cell Cycle Arrest and Cell Death by Cryptolepine in Human Lung Adenocarcinoma A549 Cells|url=https://academic.oup.com/toxsci/article/91/1/132/1672714|journal=Toxicological Sciences|language=en|volume=91|issue=1|pages=132–139|doi=10.1093/toxsci/kfj146|issn=1096-6080}}</ref>. The mechanisms involve the proteins and DNA sequences inside cells.
'''Cell cycle withdrawal''' refers to the natural stoppage of [[cell cycle]] during [[cell division]].  This stoppage could be permanent or temporary, depending on the status of [[Cell (biology)|cells]] or the activities they are undergoing<ref>{{Cite journal|last=Yang|first=Lihui|last2=Baker|first2=Nicholas E.|date=2003|title=Cell cycle withdrawal, progression, and cell survival regulation by EGFR and its effectors in the differentiating Drosophila eye|url=https://www.ncbi.nlm.nih.gov/pubmed/12636917|journal=Developmental Cell|volume=4|issue=3|pages=359–369|issn=1534-5807|pmid=12636917}}</ref>. During the process, all cell duplication process, including [[mitosis]], [[meiosis]] as well as [[DNA replication]], will be paused<ref>{{Cite journal|last=Gooderham|first=Nigel J.|last2=Zhu|first2=Huijun|date=2006-05-01|title=Mechanisms of Induction of Cell Cycle Arrest and Cell Death by Cryptolepine in Human Lung Adenocarcinoma A549 Cells|url=https://academic.oup.com/toxsci/article/91/1/132/1672714|journal=Toxicological Sciences|language=en|volume=91|issue=1|pages=132–139|doi=10.1093/toxsci/kfj146|issn=1096-6080}}</ref>. The mechanisms involve the proteins and DNA sequences inside cells.


== Permanent Cell Cycle Withdrawal ==
== Permanent Cell Cycle Withdrawal ==
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The permanent cell cycle withdrawal is mainly done by the wearing off of DNA sequences during [[S phase|S Phase]], the second stage during a DNA replication progress.<ref>{{Cite journal|last=Takeda|first=David Y|last2=Dutta|first2=Anindya|date=2005|title=DNA replication and progression through S phase|url=http://dx.doi.org/10.1038/sj.onc.1208616|journal=Oncogene|volume=24|issue=17|pages=2827–2843|doi=10.1038/sj.onc.1208616|issn=0950-9232|via=}}</ref>  Such progress occurs in the the end sequences of the whole linear [[chromosome]] named [[Telomere|telomeres]].
The permanent cell cycle withdrawal is mainly done by the wearing off of DNA sequences during [[S phase|S Phase]], the second stage during a DNA replication progress.<ref>{{Cite journal|last=Takeda|first=David Y|last2=Dutta|first2=Anindya|date=2005|title=DNA replication and progression through S phase|url=http://dx.doi.org/10.1038/sj.onc.1208616|journal=Oncogene|volume=24|issue=17|pages=2827–2843|doi=10.1038/sj.onc.1208616|issn=0950-9232|via=}}</ref>  Such progress occurs in the the end sequences of the whole linear [[chromosome]] named [[Telomere|telomeres]].


Telomeres are sequences of repetitive nucleotides which serve no genetic use.  During the replication process, the DNA replication enzymes are not able to copy the ending sequences at the telomere.  Those sequences, located at the end of the telomere and chromosome, would hence get lost gradually. Once all of these sequences have been worn out, the useful genetic information in the cell’s chromosome would also get lost.   This prevents cells from cell dividing, withdrawing cells from the cell division cycle. Therefore telomeres act as the buffer for cells to continue dividing and when telomeres are worn out, cells lose their dividing function.<ref>{{Cite journal|last=Carol|first=Greider|date=August 1990|title=Telomeres, telomerase and senescence|url=|journal=BioEssays|volume=12(8)|pages=363-369|via=}}</ref>
Telomeres are sequences of repetitive [[Nucleotide|nucleotides]] which serve no genetic use.  During the replication process, the [[DNA replication enzymes]] are not able to copy the ending sequences at the telomere.  Those sequences, located at the end of the telomere and [[chromosome]], would hence get lost gradually. Once all of these sequences have been worn out, the useful genetic information in the cell’s chromosome would also get lost.   This prevents cells from cell dividing, withdrawing cells from the cell division cycle. Therefore telomeres act as the buffer for cells to continue dividing and when telomeres are worn out, cells lose their dividing function.<ref>{{Cite journal|last=Carol|first=Greider|date=August 1990|title=Telomeres, telomerase and senescence|url=|journal=BioEssays|volume=12(8)|pages=363-369|via=}}</ref>

Not all cells carry out cell cycle withdrawal.  In some cells, such as germ cells, stem cells and white blood cells, the withdrawal process do not occur.  This is to ensure that these cells continue dividing for body growth or reproduction. Such phenomena is brought about by the presence of telomerase, which would catalyse the reaction of adding nucleotide sequences to the ends of telomeres.  It replenishes the telomeres that are lost during DNA replication, compensating for enough telomerase sequence so that the useful DNA content would not be damaged. This allows such cells to have continuous division.<ref>{{Cite journal|last=Webb|first=C. J.|last2=Wu|first2=Y.|last3=Zakian|first3=V. A.|date=2013-06-01|title=DNA Repair at Telomeres: Keeping the Ends Intact|url=http://dx.doi.org/10.1101/cshperspect.a012666|journal=Cold Spring Harbor Perspectives in Biology|volume=5|issue=6|pages=a012666–a012666|doi=10.1101/cshperspect.a012666|issn=1943-0264}}</ref>

Some organisms do not have the mechanism of cell cycle withdrawal.  Eukaryotic organisms are such examples. The DNA structure in these organisms are in the form of circular chromosomes, meaning there would be no “ends” appearing in their DNA.  Therefore the wearing off of DNA would not occur, and the genetic information would remain the same, and no withdrawal would happen.<ref>{{Cite journal|last=Boyle|first=John|date=2005|title=Lehninger principles of biochemistry (4th ed.): Nelson, D., and Cox, M.|url=http://dx.doi.org/10.1002/bmb.2005.494033010419|journal=Biochemistry and Molecular Biology Education|volume=33|issue=1|pages=74–75|doi=10.1002/bmb.2005.494033010419|issn=1470-8175|via=}}</ref>  This is to prevent the stopping of cell division in eukaryotic organisms, and hence withdrawing from the basic reproduction procedures of eukaryotic cells.


Not all cells carry out cell cycle withdrawal.  In some cells, such as [[Germ cell|germ cells]], [[Stem cell|stem cells]] and [[White blood cell|white blood cells]], the withdrawal process do not occur.  This is to ensure that these cells continue dividing for body growth or reproduction. Such phenomena is brought about by the presence of [[telomerase]], which would catalyse the reaction of adding nucleotide sequences to the ends of telomeres.  It replenishes the telomeres that are lost during DNA replication, compensating for enough telomerase sequence so that the useful DNA content would not be damaged. This allows such cells to have continuous division.<ref>{{Cite journal|last=Webb|first=C. J.|last2=Wu|first2=Y.|last3=Zakian|first3=V. A.|date=2013-06-01|title=DNA Repair at Telomeres: Keeping the Ends Intact|url=http://dx.doi.org/10.1101/cshperspect.a012666|journal=Cold Spring Harbor Perspectives in Biology|volume=5|issue=6|pages=a012666–a012666|doi=10.1101/cshperspect.a012666|issn=1943-0264}}</ref> Some other cells do not have the mechanism of cell cycle withdrawal because they don't even contain the function of [[cell division]]. [[Red blood cell]], for example, do not contain genetic material when mature, and hence will not carry out cell cycle or its withdrawal.


Some organisms also do not withdrawal mechanism.  [[Eukaryote|Eukaryotic organisms]] are such examples. The DNA structure in these organisms are in the form of [[Circular chromosome|circular chromosomes]], meaning there would be no “ends” appearing in their DNA.  Therefore the wearing off of DNA would not occur, and the genetic information would remain the same, and no withdrawal would happen.<ref>{{Cite journal|last=Boyle|first=John|date=2005|title=Lehninger principles of biochemistry (4th ed.): Nelson, D., and Cox, M.|url=http://dx.doi.org/10.1002/bmb.2005.494033010419|journal=Biochemistry and Molecular Biology Education|volume=33|issue=1|pages=74–75|doi=10.1002/bmb.2005.494033010419|issn=1470-8175|via=}}</ref>  This is to prevent the stopping of cell division in eukaryotic organisms, or even withdrawing from the basic [[reproduction]] procedures of eukaryotic cells.


'''Significance'''
'''Significance'''


There are several significance with regards to the withdrawal of cell cycle, one of which is to prevent unlimited cell division in somatic cells.  This is to prevent too many cells from accumulating inside an organism’s body, ensuring that cells in different organs are contained in a fixed proportion for achieving optimal function. <ref>{{Cite journal|last=Myster|first=Denise L|last2=Duronio|first2=Robert J|date=2000|title=Cell cycle: To differentiate or not to differentiate?|url=http://dx.doi.org/10.1016/s0960-9822(00)00435-8|journal=Current Biology|volume=10|issue=8|pages=R302–R304|doi=10.1016/s0960-9822(00)00435-8|issn=0960-9822|via=}}</ref> The stoppage of exponential growth in cells also avoids cell growth diseases, such as tumours or cancer, from occurring in human bodies.<ref>{{Cite journal|last=Ehrhardt|first=H|last2=Wachter|first2=F|last3=Grunert|first3=M|last4=Jeremias|first4=I|date=2013|title=Cell cycle-arrested tumor cells exhibit increased sensitivity towards TRAIL-induced apoptosis|url=http://dx.doi.org/10.1038/cddis.2013.179|journal=Cell Death & Disease|volume=4|issue=6|pages=e661–e661|doi=10.1038/cddis.2013.179|issn=2041-4889|via=}}</ref><ref>{{Citation|last=Brooks|first=Gavin|title=Cyclins, Cyclin-Dependent Kinases, and Cyclin-Dependent Kinase Inhibitors: Detection Methods and Activity Measurements|url=http://dx.doi.org/10.1385/1-59259-857-9:291|work=Cell Cycle Control|pages=291–298|publisher=Humana Press|isbn=1592598579|access-date=2019-04-10}}</ref> Studies have discovered the linkage between the abnormal replenishing of telomere, overactivity of telomerase, and cancer growth. <ref>{{Cite journal|last=Jafri|first=Mohammad A.|last2=Ansari|first2=Shakeel A.|last3=Alqahtani|first3=Mohammed H.|last4=Shay|first4=Jerry W.|date=2016-06-20|title=Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies|url=http://dx.doi.org/10.1186/s13073-016-0324-x|journal=Genome Medicine|volume=8|issue=1|doi=10.1186/s13073-016-0324-x|issn=1756-994X}}</ref> Here, telomere act as a barrier against cells from dividing abnormally, hence providing a stable environment for body functions. The withdrawal process also prevents diseased cells, or cells with mutated or damaged DNA, from continuing to divide and increasing the percentage of abnormal cells inside the body. It can further allow these cells to stop their functions and differentiations to undergo an automatic cell death process called apoptosis.<ref>{{Citation|title=DNA Damage-Induced Apoptosis|url=http://dx.doi.org/10.1007/springerreference_173330|work=SpringerReference|publisher=Springer-Verlag|access-date=2019-04-10}}</ref>
There are several significance with regards to the withdrawal of cell cycle, one of which is to prevent unlimited cell division in [[Somatic cell|somatic cells]].  This is to prevent too many cells from accumulating inside an organism’s body, ensuring that cells in different organs are contained in a fixed proportion for achieving optimal function. <ref>{{Cite journal|last=Myster|first=Denise L|last2=Duronio|first2=Robert J|date=2000|title=Cell cycle: To differentiate or not to differentiate?|url=http://dx.doi.org/10.1016/s0960-9822(00)00435-8|journal=Current Biology|volume=10|issue=8|pages=R302–R304|doi=10.1016/s0960-9822(00)00435-8|issn=0960-9822|via=}}</ref> The stoppage of exponential growth in cells also avoids cell growth diseases, such as [[tumours]] or [[cancer]], from occurring in organism bodies.<ref>{{Cite journal|last=Ehrhardt|first=H|last2=Wachter|first2=F|last3=Grunert|first3=M|last4=Jeremias|first4=I|date=2013|title=Cell cycle-arrested tumor cells exhibit increased sensitivity towards TRAIL-induced apoptosis|url=http://dx.doi.org/10.1038/cddis.2013.179|journal=Cell Death & Disease|volume=4|issue=6|pages=e661–e661|doi=10.1038/cddis.2013.179|issn=2041-4889|via=}}</ref><ref>{{Citation|last=Brooks|first=Gavin|title=Cyclins, Cyclin-Dependent Kinases, and Cyclin-Dependent Kinase Inhibitors: Detection Methods and Activity Measurements|url=http://dx.doi.org/10.1385/1-59259-857-9:291|work=Cell Cycle Control|pages=291–298|publisher=Humana Press|isbn=1592598579|access-date=2019-04-10}}</ref> Studies have discovered the linkage between the abnormal replenishing of telomere, overactivity of telomerase, and cancer growth. <ref>{{Cite journal|last=Jafri|first=Mohammad A.|last2=Ansari|first2=Shakeel A.|last3=Alqahtani|first3=Mohammed H.|last4=Shay|first4=Jerry W.|date=2016-06-20|title=Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies|url=http://dx.doi.org/10.1186/s13073-016-0324-x|journal=Genome Medicine|volume=8|issue=1|doi=10.1186/s13073-016-0324-x|issn=1756-994X}}</ref> Here, telomere act as a barrier against cells from dividing abnormally, hence providing a stable environment for body functions. The withdrawal process also prevents diseased cells, or cells with [[Mutation|mutated]] or damaged DNA, from continuing to divide and increasing the percentage of abnormal cells inside the body. It can further allow these cells to stop their functions and differentiations to undergo a programmed cell death process called [[apoptosis]].<ref>{{Citation|title=DNA Damage-Induced Apoptosis|url=http://dx.doi.org/10.1007/springerreference_173330|work=SpringerReference|publisher=Springer-Verlag|access-date=2019-04-10}}</ref>


Furthermore, the withdrawal process could allow cells to encounter further parts of their cell life, namely [[senescence]] and natural apoptosis. During normal body activities, cells divide, grow and [[Cellular differentiation|differentiate]] into different cell types and serve different functions. The above procedures are also known as senescence.<ref>{{Cite journal|last=McHugh|first=Domhnall|last2=Gil|first2=Jesús|date=2017-11-07|title=Senescence and aging: Causes, consequences, and therapeutic avenues|url=http://dx.doi.org/10.1083/jcb.201708092|journal=The Journal of Cell Biology|volume=217|issue=1|pages=65–77|doi=10.1083/jcb.201708092|issn=0021-9525}}</ref> After senescence, body cells would start to become old, and several functions would be lost during the process. As these cells with limited functions are inefficient in performing body activities, they are programmed to self demolition under the presence of apoptotic signals, such as [[Caspase|caspase proteins]] and [[Bcl-2 family|Bcl-2 family regulation proteins]].<ref>{{Cite web|url=http://dx.doi.org/10.2210/pdb1lxl/pdb|title=NMR STRUCTURE OF BCL-XL, AN INHIBITOR OF PROGRAMMED CELL DEATH, MINIMIZED AVERAGE STRUCTURE|last=Muchmore|first=S.W.|last2=Sattler|first2=M.|date=1997-04-21|website=dx.doi.org|access-date=2019-04-10|last3=Liang|first3=H.|last4=Meadows|first4=R.P.|last5=Harlan|first5=J.E.|last6=Yoon|first6=H.S.|last7=Nettesheim|first7=D.|last8=Chang|first8=B.S.|last9=Thompson|first9=C.B.}}</ref> Before such process, the cell cycle withdrawal ensures that these aged cells are not divided into other daughter cells before death, so as to maintain the age level of cells in organisms to perform efficient body activities.<ref>{{Cite journal|last=Campisi|first=Judith|date=2008-06|title=Aging and cancer cell biology, 2008|url=http://dx.doi.org/10.1111/j.1474-9726.2008.00383.x|journal=Aging Cell|volume=7|issue=3|pages=281–284|doi=10.1111/j.1474-9726.2008.00383.x|issn=1474-9718}}</ref>
Furthermore, the withdrawal process could allow cells to encounter further parts of their cell life, namely senescence and natural apoptosis.


'''References'''
'''References'''

Revision as of 13:53, 10 April 2019

Cell Cycle Withdrawal

Cell cycle withdrawal refers to the natural stoppage of cell cycle during cell division.  This stoppage could be permanent or temporary, depending on the status of cells or the activities they are undergoing[1]. During the process, all cell duplication process, including mitosis, meiosis as well as DNA replication, will be paused[2]. The mechanisms involve the proteins and DNA sequences inside cells.

Permanent Cell Cycle Withdrawal

Permanent cell cycle withdrawal refers to the forever stoppage in divisions of cells.  In organisms, cells do not divide endlessly.[3]  Certain mechanisms are present to prevent cells from indefinite division, which is mostly done by programmed failure in DNA synthesis.  By adapting the above mechanism, cells are prevented from over dividing. The process also enables cells to proceed to senescence, which are further stages of cell life and growth.[4]

Mechanism

The permanent cell cycle withdrawal is mainly done by the wearing off of DNA sequences during S Phase, the second stage during a DNA replication progress.[5]  Such progress occurs in the the end sequences of the whole linear chromosome named telomeres.

Telomeres are sequences of repetitive nucleotides which serve no genetic use.  During the replication process, the DNA replication enzymes are not able to copy the ending sequences at the telomere.  Those sequences, located at the end of the telomere and chromosome, would hence get lost gradually. Once all of these sequences have been worn out, the useful genetic information in the cell’s chromosome would also get lost.   This prevents cells from cell dividing, withdrawing cells from the cell division cycle. Therefore telomeres act as the buffer for cells to continue dividing and when telomeres are worn out, cells lose their dividing function.[6]

Not all cells carry out cell cycle withdrawal.  In some cells, such as germ cells, stem cells and white blood cells, the withdrawal process do not occur.  This is to ensure that these cells continue dividing for body growth or reproduction. Such phenomena is brought about by the presence of telomerase, which would catalyse the reaction of adding nucleotide sequences to the ends of telomeres.  It replenishes the telomeres that are lost during DNA replication, compensating for enough telomerase sequence so that the useful DNA content would not be damaged. This allows such cells to have continuous division.[7] Some other cells do not have the mechanism of cell cycle withdrawal because they don't even contain the function of cell division. Red blood cell, for example, do not contain genetic material when mature, and hence will not carry out cell cycle or its withdrawal.

Some organisms also do not withdrawal mechanism.  Eukaryotic organisms are such examples. The DNA structure in these organisms are in the form of circular chromosomes, meaning there would be no “ends” appearing in their DNA.  Therefore the wearing off of DNA would not occur, and the genetic information would remain the same, and no withdrawal would happen.[8]  This is to prevent the stopping of cell division in eukaryotic organisms, or even withdrawing from the basic reproduction procedures of eukaryotic cells.

Significance

There are several significance with regards to the withdrawal of cell cycle, one of which is to prevent unlimited cell division in somatic cells.  This is to prevent too many cells from accumulating inside an organism’s body, ensuring that cells in different organs are contained in a fixed proportion for achieving optimal function. [9] The stoppage of exponential growth in cells also avoids cell growth diseases, such as tumours or cancer, from occurring in organism bodies.[10][11] Studies have discovered the linkage between the abnormal replenishing of telomere, overactivity of telomerase, and cancer growth. [12] Here, telomere act as a barrier against cells from dividing abnormally, hence providing a stable environment for body functions. The withdrawal process also prevents diseased cells, or cells with mutated or damaged DNA, from continuing to divide and increasing the percentage of abnormal cells inside the body. It can further allow these cells to stop their functions and differentiations to undergo a programmed cell death process called apoptosis.[13]

Furthermore, the withdrawal process could allow cells to encounter further parts of their cell life, namely senescence and natural apoptosis. During normal body activities, cells divide, grow and differentiate into different cell types and serve different functions. The above procedures are also known as senescence.[14] After senescence, body cells would start to become old, and several functions would be lost during the process. As these cells with limited functions are inefficient in performing body activities, they are programmed to self demolition under the presence of apoptotic signals, such as caspase proteins and Bcl-2 family regulation proteins.[15] Before such process, the cell cycle withdrawal ensures that these aged cells are not divided into other daughter cells before death, so as to maintain the age level of cells in organisms to perform efficient body activities.[16]

References

  1. ^ Yang, Lihui; Baker, Nicholas E. (2003). "Cell cycle withdrawal, progression, and cell survival regulation by EGFR and its effectors in the differentiating Drosophila eye". Developmental Cell. 4 (3): 359–369. ISSN 1534-5807. PMID 12636917.
  2. ^ Gooderham, Nigel J.; Zhu, Huijun (2006-05-01). "Mechanisms of Induction of Cell Cycle Arrest and Cell Death by Cryptolepine in Human Lung Adenocarcinoma A549 Cells". Toxicological Sciences. 91 (1): 132–139. doi:10.1093/toxsci/kfj146. ISSN 1096-6080.
  3. ^ Clark, William R., 1938- (2002). A means to an end : the biological basis of aging and death. Oxford University Press. ISBN 9780198029113. OCLC 60932736.{{cite book}}: CS1 maint: multiple names: authors list (link) CS1 maint: numeric names: authors list (link)
  4. ^ White, Ryan R.; Vijg, Jan (2016). "Do DNA Double-Strand Breaks Drive Aging?". Molecular Cell. 63 (5): 729–738. doi:10.1016/j.molcel.2016.08.004. ISSN 1097-2765.
  5. ^ Takeda, David Y; Dutta, Anindya (2005). "DNA replication and progression through S phase". Oncogene. 24 (17): 2827–2843. doi:10.1038/sj.onc.1208616. ISSN 0950-9232.
  6. ^ Carol, Greider (August 1990). "Telomeres, telomerase and senescence". BioEssays. 12(8): 363–369.
  7. ^ Webb, C. J.; Wu, Y.; Zakian, V. A. (2013-06-01). "DNA Repair at Telomeres: Keeping the Ends Intact". Cold Spring Harbor Perspectives in Biology. 5 (6): a012666–a012666. doi:10.1101/cshperspect.a012666. ISSN 1943-0264.
  8. ^ Boyle, John (2005). "Lehninger principles of biochemistry (4th ed.): Nelson, D., and Cox, M." Biochemistry and Molecular Biology Education. 33 (1): 74–75. doi:10.1002/bmb.2005.494033010419. ISSN 1470-8175.
  9. ^ Myster, Denise L; Duronio, Robert J (2000). "Cell cycle: To differentiate or not to differentiate?". Current Biology. 10 (8): R302–R304. doi:10.1016/s0960-9822(00)00435-8. ISSN 0960-9822.
  10. ^ Ehrhardt, H; Wachter, F; Grunert, M; Jeremias, I (2013). "Cell cycle-arrested tumor cells exhibit increased sensitivity towards TRAIL-induced apoptosis". Cell Death & Disease. 4 (6): e661–e661. doi:10.1038/cddis.2013.179. ISSN 2041-4889.
  11. ^ Brooks, Gavin, "Cyclins, Cyclin-Dependent Kinases, and Cyclin-Dependent Kinase Inhibitors: Detection Methods and Activity Measurements", Cell Cycle Control, Humana Press, pp. 291–298, ISBN 1592598579, retrieved 2019-04-10
  12. ^ Jafri, Mohammad A.; Ansari, Shakeel A.; Alqahtani, Mohammed H.; Shay, Jerry W. (2016-06-20). "Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies". Genome Medicine. 8 (1). doi:10.1186/s13073-016-0324-x. ISSN 1756-994X.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  13. ^ "DNA Damage-Induced Apoptosis", SpringerReference, Springer-Verlag, retrieved 2019-04-10
  14. ^ McHugh, Domhnall; Gil, Jesús (2017-11-07). "Senescence and aging: Causes, consequences, and therapeutic avenues". The Journal of Cell Biology. 217 (1): 65–77. doi:10.1083/jcb.201708092. ISSN 0021-9525.
  15. ^ Muchmore, S.W.; Sattler, M.; Liang, H.; Meadows, R.P.; Harlan, J.E.; Yoon, H.S.; Nettesheim, D.; Chang, B.S.; Thompson, C.B. (1997-04-21). "NMR STRUCTURE OF BCL-XL, AN INHIBITOR OF PROGRAMMED CELL DEATH, MINIMIZED AVERAGE STRUCTURE". dx.doi.org. Retrieved 2019-04-10.
  16. ^ Campisi, Judith (2008-06). "Aging and cancer cell biology, 2008". Aging Cell. 7 (3): 281–284. doi:10.1111/j.1474-9726.2008.00383.x. ISSN 1474-9718. {{cite journal}}: Check date values in: |date= (help)