Regulation of Signal Transduction in Human Cell Research by Nariyoshi Shinomiya Hiroaki Kataoka & Qian Xie

Author:Nariyoshi Shinomiya, Hiroaki Kataoka & Qian Xie
Language: eng
Format: epub
Publisher: Springer Singapore, Singapore

6.2.3 Integrating the Signals: Checkpoint Regulation of DNA Repair

When considering the DDR, it is essential to consider the transiently activated checkpoints as well as its regulation of DNA repair as coordination between the two systems is indispensable for successful maintenance of genomes. Also importantly, the coordination is likely cell cycle-dependent in most cases. While this is based on the premise that some DNA repair protein expression is limited to certain phases of the cell cycle, this concept has much broader implications when investigating integrated control on pathway selection and repair efficiency [80–82].

The checkpoint control of DNA repair is seen at multiple levels stemming from ATM, ATR, and DNA-PK activity. For instance, ATR regulates NER following UV irradiation through direct binding and phosphorylation of XPA at Ser196 promoting its stability and nuclear import following UV irradiation [83–86]. This process is dependent on PKA phosphorylation of ATR at Ser435, and loss of this site leads to reduced ATR-XPA binding as well as delayed XPA recruitment to sites of DNA damage [87]. This effect is found to occur primarily in the S phase of the cell cycle and to be p53 dependent. This is in contrast to XPA nuclear import during G1 or G2 phases in which XPA nuclear import is p53/ATR independent; in G1, the UV-induced import is muted, while in G2, XPA accumulates in the nucleus regardless of DNA damage [88]. Checkpoint control of NER is further enacted by p53 which is a target of all three apical kinases as well as secondary kinases, Chk1 and Chk2. p53 upregulates gene expression of NER proteins following a variety of genomic insults resulting in increased DDB2, XPC, XPF, and XPG levels [89, 90]. Active p53 is also known to be involved in the recruitment of XPC as well as TFIIH to sites of UV damage where it facilitates improved DNA damage recognition and repair [91, 92].

Checkpoint control of DNA repair also extends to BER, HR, and NHEJ. BER activity is modulated through activated p53’s direct binding to three BER enzymes: APE/REF1, OGG1, and DNA polymerase beta. This binding stimulates the recognition, excision, and respective repair activities of these enzymes leading to enhanced BER [93, 94]. ATM, ATR, and DNA-PK all collaborate to promote effective HR through the regulation of the RPA-p53 interaction [30]. The interaction of RPA-p53 typically promotes NHEJ through sequestration of RPA; however, Ser37 and Ser46 phosphorylation of p53 by ATM and ATR, respectively, along with RPA32 phosphorylation by DNA-PK leads to dissociation of the RPA-p53 complex and a switching to HR [30, 95].

In addition to the effects listed previously, direct cycle control of DNA repair occurs through cyclic expression of repair factors and regulation by cyclin dependent kinases. In brief, many proteins involved in DNA repair are only expressed at certain points throughout the cell cycle. For instance, gene-encoding proteins for mismatch repair are almost exclusively expressed in S phase, whereas most genes for ICLR are expressed in S-M phases. For more information regarding cell cycle expression of DNA repair proteins, we would point interested readers to the recent work by Mjelle et al.

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