Journal
MOLECULAR CELL
Volume 22, Issue 3, Pages 407-413Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2006.03.022
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Funding
- NCI NIH HHS [CA099194] Funding Source: Medline
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Regulation of mutation rates is critical for maintaining genome stability and controlling cancer risk. A special challenge to this regulation is the presence of multiple mutagenic DNA polymerases in mammals. These polymerases function in translesion DNA synthesis (TLS), an error-prone DNA repair process that involves DNA synthesis across DNA lesions. We found that in mammalian cells TLS is controlled by the tumor suppressor p53, and by the cell cycle inhibitor p21 via its PCNA-interacting domain, to maintain a low mutagenic load at the price of reduced repair efficiency. This regulation may be mediated by binding of p2l to PCNA and via DNA damage-induced ubiquitination of PCNA, which is stimulated by p53 and p2l. Loss of this regulation by inactivation of p53 or p2l causes an out of control lesion-bypass activity, which increases the mutational load and might therefore play a role in pathogenic processes caused by genetic instability.
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