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DNA methyltransferases, DNA damage repair, and cancer - PubMed

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DNA methyltransferases, DNA damage repair, and cancer

Bilian Jin et al. Adv Exp Med Biol. 2013.

Abstract

The maintenance DNA methyltransferase (DNMT) 1 and the de novo methyltransferases DNMT3A and DNMT3B are all essential for mammalian development. DNA methylation, catalyzed by the DNMTs, plays an important role in maintaining genome stability. Aberrant expression of DNMTs and disruption of DNA methylation patterns are closely associated with many forms of cancer, although the exact mechanisms underlying this link remain elusive. DNA damage repair systems have evolved to act as a genome-wide surveillance mechanism to maintain chromosome integrity by recognizing and repairing both exogenous and endogenous DNA insults. Impairment of these systems gives rise to mutations and directly contributes to tumorigenesis. Evidence is mounting for a direct link between DNMTs, DNA methylation, and DNA damage repair systems, which provide new insight into the development of cancer. Like tumor suppressor genes, an array of DNA repair genes frequently sustain promoter hypermethylation in a variety of tumors. In addition, DNMT1, but not the DNMT3s, appear to function coordinately with DNA damage repair pathways to protect cells from sustaining mutagenic events, which is very likely through a DNA methylation-independent mechanism. This chapter is focused on reviewing the links between DNA methylation and the DNA damage response.

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Figures

Fig. 1
Fig. 1. Impact of DNMT1 on MMR and DDR

DNMT1 may promote stabilization of microsatellites via methylation of CpG repeats and it also interacts with DNA repair proteins via third-party mediators (e.g. MBD4 and PCNA). Moreover, deficiency in DNMT1 leads to activation of PARP signaling, eventually resulting in MMR protein cleavage. DNMT1 is also closely associated with DDR. Inactivation of DNMT1 may induce several changes to DNA and/or chromatin including increased DNA fragility, disruption of replication foci, and accumulation of hemimethylated DNA, which may be recognized as “damage” and activate the DDR. Strong support for a direct link between DNMT1 and DDR comes from the identification of several protein-protein interactions involving DNMT1 and DDR proteins. DNMT1 is recruited to sites of DNA damage via its interaction with PCNA and 9-1-1. DNMT1 is also capable of binding CHK1 and p53, which promote cell cycle arrest and apoptosis, respectively.

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