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Breakage of both chromosomal DNA strands creates unique problems for DNA repair. Here, Luthman et al. show that for some broken ends, the two strand breaks are repaired in parallel, while for other ends one strand must be repaired before the other.

Polymerase delta is required for multiple steps in polymerase theta-dependent repair of chromosome breaks, a pathway targeted in cancer therapy.

DNA double strand breaks result in various types of damaged termini and are resolved by non-homologous end joining, but how cells coordinate the different steps that occur during repair is not clear. Here the authors show that a DNA ligase coordinates processing prior to the ligation step to limit errors.

Poly(ADP) ribose polymerase (PARP) activity promotes, but is not required for, chromosome break repair by polymerase theta-mediated end joining (TMEJ). PARP activity promotes TMEJ by stimulating resection, a process that controls pathway choice.

Polymerase theta is a widely conserved DNA polymerase that mediates Theta Mediated End Joining. Here authors present a synthetic lethal CRISPR screen to identify DDR gene mutations that induce cellular addiction to Pol theta.

Most agents that generate breaks in DNA leave 'dirty ends' that cannot be joined immediately; instead, intervening steps are required to restore the integrity of nucleotides at the break. Here it is shown that the non-homologous end joining pathway requires a 5′-dRP/AP lyase activity to remove abasic sites at double-strand breaks. Surprisingly, this activity is catalysed by the Ku70 protein, which, together with its partner Ku86, had been thought only to recognize broken DNA ends and to recruit other factors that process ends.

Using X-ray crystallography and nonhomologous end-joining assays, this study reveals structural features within Polλ that provide it with the ability to bridge and stabilize tenuous DNA double-strand break ends, allowing for religation.

Polymerase μ (Polμ) participates in the repair of DNA double-strand breaks (DSBs) via the nonhomologous end-joining (NHEJ) pathway. Here, the authors determine the crystal structure of a pre-catalytic ternary complex of human Polμ with a bound DSB substrate and they obtain further mechanistic insights by allowing the insertion reaction to proceed in crystallo, which enabled them to determine a Polμ structure with incomplete incorporation and the structure of the post-catalytic nicked state.

Retrotransposons hijack the alternative end-joining DNA repair process of the host for a circularization step to synthesize their second-strand DNA.

X family DNA polymerases can fill short DNA gaps by binding both the 5′ and 3′ ends of the gap. What happens to the template strand is now revealed in the crystal structure of human polymerase λ bound to a 2-nucleotide gap substrate. The template strand is scrunched, with the additional base in an extrahelical position going into an enzyme pocket.

DNA polymerase μ promotes nonhomologous end joining (NHEJ) of DNA double-strand breaks. Crystal structures of truncated human DNA polymerase μ with and without a gapped DNA substrate provide the first structural evidence that the loop 1 domain is repositioned to permit template binding and that catalysis occurs without additional enzyme repositioning.

Tyrosyl-DNA phosphodiesterase 2 (Tdp2) processes DNA termini with a 5′-phosphotyrosyl–linked topoisomerase II adduct, such as those stabilized by chemotherapeutic drugs anthracyclines and etoposides, by direct reversal of the 5′-phosphotyrosyl linkage. Now crystal structures of mouse Tdp2–DNA complexes, along with mutagenesis and functional analyses, reveal how Tdp2 recognizes and reverses such adduction.

AIM2 suppresses colon tumorigenesis, independently of the inflammasome and IL-1β, by interacting with DNA-PK and inhibiting Akt activation.

The histone methyltransferases E(Z) and Ezh2 may control developmental fate by regulating homeobox gene expression. Emerging evidence suggests Ezh2 also plays a role in B cell development by controlling V(D)J recombination.

Non-homologous DNA end joining (NHEJ) is the main repair pathway of DNA double-strand breaks. Recent studies show that synapsis — the crucial pairing of DNA ends — is performed by several mechanisms, and this insight can now be integrated with updates on the DNA end processing and ligation steps of NHEJ, and with NHEJ-related human diseases.

DNA polymerase theta (Polθ)-mediated end joining is a recently characterized DNA repair pathway that functions in various cellular contexts to repair DNA double-strand breaks that are not repaired by other pathways. Polθ-mediated end joining both helps maintain the genome and causes genome instability, and is an emerging therapeutic target in cancer.