DNA polymerases in nonhomologous end joining: Are there any benefits to standing out from the crowd?

Abstract

Chromosome breaks, often with damaged or missing DNA flanking the break site, are an important threat to genome stability. They are repaired in vertebrates primarily by nonhomologous end joining (NHEJ). NHEJ is unique among the major DNA repair pathways in that a continuous template cannot be used by DNA polymerases to instruct replacement of damaged or lost DNA. Nevertheless, at least 3 out of the 17 mammalian DNA polymerases are specifically employed by NHEJ. Biochemical and structural studies are further revealing how each of the polymerases employed by NHEJ possesses distinct and sophisticated means to overcome the barriers this pathway presents to polymerase activity. Still unclear, though, is how the resulting network of overlapping and nonoverlapping polymerase activities contributes to repair in cells. Environ. Mol. Mutagen. 53:741-751, 2012. V V C 2012 Wiley Periodicals, Inc.

Non-homologous end joining: Emerging themes and unanswered questions

“…In addition, Ku80 interacts with APLF (aprataxin and PNKP-like factor, also called PALF for PNKP and aprataxin-like factor), which enhances NHEJ, stimulating DSB end ligation by DNA ligase IV [25, 26]. Ku also interacts with the Werner's syndrome helicase [27] as well as with DNA polymerase mu and lambda [28, 29] suggesting roles in the recruitment or retention of additional end-processing factors at the break (Fig. 1).…”

“…Additional end processing in NHEJ is carried out by DNA polymerases mu and lambda (and TdT in V(D)J recombination) which interact with Ku and the XRCC4-DNA ligase IV complex and perform gap filling roles [29]. Artemis, a structure specific endonuclease interacts with DNA-PKcs and plays a critical role in opening DNA hairpin coding ends in V(D)J recombination [21, 46].…”

Yeast Pol4 Promotes Tel1-Regulated Chromosomal Translocations

“…NHEJ also involves accessory factors such as DNA polymerases belonging to the PolX family [10]. Among mammalian PolX polymerases, Polλ and Polμ are specialized DNA polymerases with a large capacity to use imperfect template-primer DNA substrates.…”

Repair of Double-Strand Breaks by End Joining

“…4C). Structural studies of mammalian Pol l and Pol m, themselves also c-NHEJ enzymes, provide insight into this function Nick McElhinny et al 2005;Moon et al 2007;Ramsden and Asagoshi 2012). The catalytic domains of these Pol X polymerases are bipartite with binding pockets for the 5 0 and 3 0 termini of the broken strand whose gap is being filled (Fig.…”