Editing Cell division (section)

== DNA damage repair in the cell cycle ==
DNA damage is detected and repaired at various points in the cell cycle. The [[Cell cycle checkpoint|G1/S checkpoint, G2/M checkpoint, and the checkpoint between metaphase and anaphase]] all monitor for DNA damage and halt cell division by inhibiting different cyclin-CDK complexes.  The [[P53|p53 tumor-suppressor protein]] plays a crucial role at the G1/S checkpoint and the G2/M checkpoint. Activated p53 proteins result in the expression of many proteins that are important in cell cycle arrest, repair, and apoptosis.  At the G1/S checkpoint, p53 acts to ensure that the cell is ready for DNA replication, while at the G2/M checkpoint p53 acts to ensure that the cells have properly duplicated their content before entering mitosis.<ref>{{Cite book |last1=Senturk |first1=Emir |last2=Manfredi |first2=James J. |title=P53 Protocols |date=2013 |chapter=p53 and Cell Cycle Effects After DNA Damage |series=Methods in Molecular Biology (Clifton, N.J.) |volume=962 |pages=49–61 |doi=10.1007/978-1-62703-236-0_4 |issn=1064-3745 |pmc=4712920 |pmid=23150436|isbn=978-1-62703-235-3 }}</ref>

Specifically, when DNA damage is present, [[Ataxia telangiectasia and Rad3 related|ATM and ATR kinases]] are activated, activating various checkpoint kinases.<ref>{{Cite journal |last1=Ding |first1=Lei |last2=Cao |first2=Jiaqi |last3=Lin |first3=Wen |last4=Chen |first4=Hongjian |last5=Xiong |first5=Xianhui |last6=Ao |first6=Hongshun |last7=Yu |first7=Min |last8=Lin |first8=Jie |last9=Cui |first9=Qinghua |date=2020-03-13 |title=The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer |journal=International Journal of Molecular Sciences |volume=21 |issue=6 |pages=1960 |doi=10.3390/ijms21061960 |issn=1422-0067 |pmc=7139603 |pmid=32183020 |doi-access=free }}</ref> These checkpoint kinases phosphorylate p53, which stimulates the production of different enzymes associated with DNA repair.<ref>{{Cite journal |last1=Williams |first1=Ashley B. |last2=Schumacher |first2=Björn |date=2016 |title=p53 in the DNA-Damage-Repair Process |journal=Cold Spring Harbor Perspectives in Medicine |volume=6 |issue=5 |pages=a026070 |doi=10.1101/cshperspect.a026070 |issn=2157-1422 |pmc=4852800 |pmid=27048304}}</ref> Activated p53 also upregulates [[p21]], which inhibits various cyclin-cdk complexes. These cyclin-cdk complexes [[phosphorylate]] the [[Retinoblastoma protein|Retinoblastoma (Rb) protein]], a tumor suppressor bound with the E2F family of transcription factors. The binding of this Rb protein ensures that cells do not enter the S phase prematurely; however, if it is not able to be phosphorylated by these cyclin-cdk complexes, the protein will remain, and the cell will be halted in the G1 phase of the cell cycle.<ref>{{Cite journal |last=Engeland |first=Kurt |date=2022 |title=Cell cycle regulation: p53-p21-RB signaling |journal=Cell Death & Differentiation |language=en |volume=29 |issue=5 |pages=946–960 |doi=10.1038/s41418-022-00988-z |pmid=35361964 |pmc=9090780 |issn=1476-5403|doi-access=free }}</ref>

If DNA is damaged, the cell can also alter the Akt pathway in which [[Bcl-2-associated death promoter|BAD]] is phosphorylated and dissociated from Bcl2, thus inhibiting apoptosis. If this pathway is altered by a loss of function mutation in Akt or Bcl2, then the cell with damaged DNA will be forced to undergo apoptosis.<ref>{{Cite journal |last1=Ruvolo |first1=P. P. |last2=Deng |first2=X. |last3=May |first3=W. S. |date=2001 |title=Phosphorylation of Bcl2 and regulation of apoptosis |url=https://www.nature.com/articles/2402090 |journal=Leukemia |language=en |volume=15 |issue=4 |pages=515–522 |doi=10.1038/sj.leu.2402090 |pmid=11368354 |s2cid=2079715 |issn=1476-5551}}</ref> If the DNA damage cannot be repaired, activated p53 can induce cell death by [[apoptosis]]. It can do so by activating the [[P53 upregulated modulator of apoptosis|p53 upregulated modulator of apoptosis (PUMA)]]. PUMA is a pro-apoptotic protein that rapidly induces apoptosis by inhibiting the anti-apoptotic [[Bcl-2]] family members.<ref>{{Cite journal |last1=Jabbour |first1=A. M. |last2=Heraud |first2=J. E. |last3=Daunt |first3=C. P. |last4=Kaufmann |first4=T. |last5=Sandow |first5=J. |last6=O'Reilly |first6=L. A. |last7=Callus |first7=B. A. |last8=Lopez |first8=A. |last9=Strasser |first9=A. |last10=Vaux |first10=D. L. |last11=Ekert |first11=P. G. |date=2009 |title=Puma indirectly activates Bax to cause apoptosis in the absence of Bid or Bim |journal=Cell Death & Differentiation |language=en |volume=16 |issue=4 |pages=555–563 |doi=10.1038/cdd.2008.179 |pmid=19079139 |issn=1476-5403|doi-access=free }}</ref>