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DNA2 suppresses recombination-restarted replication and checkpoint activation at stalled forks, and its loss triggers recombination-dependent synthesis, checkpoint signalling and cell-cycle exit, highlighting its essential role in proliferation and growth failure in primordial dwarfism.

Keith Caldecott, Bert de Vries, Sherif El-Khamisy, Gianpiero Cavalleri and colleagues identify homozygous TDP2 mutations in individuals with intellectual disability, seizures and ataxia. Their follow-up studies suggest that TDP2 is required to maintain normal transcription in response to the DNA double-strand breaks induced by abortive TOP2 activity.

Certain antimetabolites used to treat cancer are more neurotoxic than others, and it is now shown that this is due to their greater tendency to generate DNA double-stranded breaks, whereas less neurotoxic agents induce single-stranded breaks.

Single-strand breaks are the most common type of DNA damage that arise in cells. Keith Caldecott discusses the molecular mechanisms and organization of the pathways that repair these lesions and the link between defects in these pathways and hereditary neurodegenerative disease.

The authors identify a DNA-protein crosslink (DPC) repair pathway orchestrated by poly-ADP-ribosylation. In this process, PARP1 PARylates the DPC, marking it for removal by proteolysis. Consequently, PARP1 facilitates the repair of DPCs located next to DNA breaks, such as topoisomerase 1-DPCs.

Three structures were recently reported for tyrosyl DNA phosphodiesterase 2 (Tdp2), a protein that protects the metazoan genome from shredding following abortive topoisomerase activity. The physiological significance of these findings is discussed here.

Biochemical and cell-based assays reveal that PARP inhibitors impede the maturation of nascent DNA strands during DNA replication, and implicate unligated Okazaki fragments and other nascent strand discontinuities in the cytotoxicity of these anti-cancer compounds.

DNA single-strand breaks in neurons accumulate at high levelsin functional enhancers.

Defects in DNA single-strand break repair are associated with neurodegenerative disease. Here the authors reveal that mutations in ARH3 interfere with the catabolism of mono-(ADP-ribose) and lead to its accumulation on core histones following repair of endogenous or exogenous DNA single-strand breaks.

Werner syndrome is a progeroid disease characterised by genetic instability due to mutations to the WRN helicase/exonuclease. Here the authors define a novel Ku binding motif (KBM) and show that two such motifs facilitate the involvement of WRN in DNA double-strand break repair.

Adamowicz et al. report that toxic PARP1 activity, induced by ataxia-associated mutations in XRCC1, impairs the recovery of global transcription during DNA base excision repair by promoting aberrant recruitment and activity of the histone ubiquitin protease USP3.

DNA double-strand breaks (DSBs) induced by topoisomerase II (TOP2) are rejoined by TDP2-dependent non-homologous end-joining (NHEJ) but whether this promotes or suppresses translocations is not clear. Here the authors show that TDP2 suppresses chromosome translocations from DSBs introduced during gene transcription.

Chromosomal single-strand DNA breaks occur frequently and require repair to avoid disease outcomes. Here, the authors show that in bird cells, PARP3 accelerates this repair, and use structural biology and cell biology techniques to reveal details of the mechanism of action.

Aprataxin cleans up unfinished DNA ligation intermediates. By cleaving off an adenylate group at the site of a ligatable nick, aprataxin generates ends that can then be re-ligated. This suggests that neurodegeneration results from the accumulation of these intermediates in post-mitotic neuronal cells.

Mutations in BRAT1 are associated with neurodevelopmental delay and neurodegeneration. Here, the authors show that BRAT1 is a component of Integrator and is important for processing of specific RNAs. They further demonstrate that BRAT1 mutant patient-derived cells exhibit reduced levels of the Integrator catalytic subunit and increased levels of misprocessed UsnRNAs and impaired RNA processing.

Two recent reports describe potentially novel therapeutic approaches for treating tumors arising from mutations in the tumor suppressor genes BRCA1 and BRCA2. These studies support the idea that selective killing of tumor cells can be achieved by targeting a specific DNA repair pathway on which an individual tumor type has become dependent.

Defects in DNA single strand break repair (SSBR) can cause neurodegeneration. To better understand the function of SSBR in the nervous system, the authors ablated Xrcc1 in all of the neural progenitors of developing mice. This revealed that the postnatal differentiation of several types of cerebellar interneurons is particularly dependent on SSBR.

The mechanism of topoisomerase action involves making a transient break in DNA, which, if it occurs near another DNA lesion, can persist, with the topoisomerase attached the 3′ or 5′ end by a phosphotyrosyl bond. If the DNA termini are not liberated from the topoisomerase, cancer and neurodegenerative disease may result. A human enzyme that cleaves 3′-phosphotyrosyl bonds has already been identified; a complementary enzyme that cleaves 5′-phosphotyrosyl bonds is now reported.

Biallelic mutations in human XRCC1 are associated with ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia.

Normal cellular processes can cause DNA breaks which become substrates for the cell’s DNA repair machinery. Focusing on neurons, this Perspective article explores the role of this ‘programmed’ DNA damage and its repair in health, ageing and neurodegenerative disease.

Christopher Walsh and colleagues describe a new recessive genetic disease characterized by microcephaly, early-onset intractable seizures and developmental delay (MCSZ). The authors identify mutations in PNKP that result in this severe disease and show that PNKP mutations disrupt DNA repair.

Recently, ZATT (also known as ZNF451 or Zpf451) was reported by Schellenberg et al. to aid the removal of Topoisomerase II cleavage complexes by stimulating the phosphodiesterase activity of Tyrosyl DNA Phosphodiesterase 2. Although the full implication of this discovery is unknown, it will help us understand how cells respond to topoisomerase-induced genome damage and chemotherapeutic topoisomerase 'poisons'.