Post-translesion synthesis repair

Unrepaired DNA nucleotide lesions, derived from endogenous (radical oxygen species, base decay, etc) or exogenous (sunlight, smoke, alcohol, etc.) sources can compromise cellular and organismal health. Cellular responses to DNA damage range from DNA damage responses (DDR) including checkpoints, senescence 1and apoptosis, to nucleotide substitutions and genomic rearrangements [1]. A common intermediate in all these responses are the lesion-containing single-stranded DNA (ssDNA) tracts that originate from the inability of replicative DNA polymerases to bypass damaged templates [2]. Persistent ssDNA tracts recruit the heterotrimeric RPA protein and the ATR/ATRIP DNA kinase that initiates DDR by phosphorylating various proteins, including the CHK1 DNA damage signaling kinase [1, 3]. When ssDNA tracts persist they are at risk to collapse into recombinogenic double-strand DNA breaks [2]. To avert the induction of DDR and of DSB, specialized DNA translesion synthesis (TLS) polymerases fill the lesion-containing ssDNA tracts. Unfortunately, TLS polymerases frequently insert an incorrect nucleotide opposite the damaged nucleotide, ultimately resulting in a nucleotide substitution. It is important, therefore, to keep TLS in check. Mechanisms that control TLS include the restricted recruitment of TLS polymerases, the selective expression or posttranslational modification of TLS polymerases or, possibly, correction of TLS errors by the proofreading activity of the replicative polymerases [3]. We recently have unveiled a new mechanism that controls mutagenic TLS, and also DDR induction, in response to physiologically relevant DNA lesion densities [4]. This mechanism utilizes MutSα, a core component of the DNA mismatch repair (MMR) pathway. During canonical MMR, MutSα recognizes and binds misincorporations by the replicative DNA polymerases opposite normal or slightly modified nucleotides. This initiates a repair cascade that involves (i) MutLα-mediated incision of the nascent DNA strand, 5’ of the mismatch, (ii) the exonucleolytic removal of the nascent DNA strand containing the misincorporation, and (iii) resynthesis [5]. Loss of MMR results in a spontaneous mutator phenotype that originates cancer in the human Lynch syndrome. It has long been known that MMR proteins additionally are involved in provoking DDR to nucleotide lesions that severely disrupt the helical structure of DNA, including polycyclic aromatic hydrocarbons and ultraviolet (UV) light [6]. It has been hypothesized that this response reflects binding of MutSα and MutLα to damaged nucleotides, followed by the direct activation of the DDR machinery [5]. However, although MutSα and MutLα can indeed recruit ATR/ATRIP and CHK1, there is no good evidence in favor of the binding of MutSα to Editorial