DNA Strand Break Repair and Human Genetic Disease


Deoxyribonucleic acid (DNA) contains the genetic information for proper functioning of cells and alterations in the DNA sequence constitute a threat to genetic stability and cell survival. DNA is constantly exposed to exogenous and endogenous DNA‐damaging agents. Among the different types of DNA damage, single‐strand breaks (SSBs) and double‐strand breaks (DSBs) are a source of genetic instability. To minimise the impact of these lesions, cells have evolved various DNA repair mechanisms depending on the kind of DNA damage. The importance of DNA‐strand break repair is highlighted by the observation that many proteins involved in DNA repair are mutated in a wide variety of cancers and in different hereditary syndromes. These disorders display a variety of features. Notably, syndromes related with defects in SSB repair exhibit a pathology restricted to cerebellar ataxia and neurodegeneration, whereas DSB repair syndromes exhibit a more diverse pathology and can include developmental abnormalities, microcephaly and cancer predisposition.

Key Concepts

  • The DNA damage response (DDR) is a signal transduction pathway that starts with the sensing of the damage and coordinates cell cycle, repair and apoptosis.
  • DDR plays an important role in development and preservation of genome stability and, consequently, is crucial for cancer prevention and normal ageing.
  • Many proteins involved in DNA repair pathways are mutated in a wide variety of cancers and in different types of hereditary diseases.
  • Homologous recombination is a DNA repair pathway linked to replication and devoted to the repair of DNA breaks using an intact DNA template to copy information.
  • Nonhomologous end‐joining (NHEJ) is a double‐strand break repair pathway that ligates the two ends without using any DNA template.
  • DSB repair syndromes exhibit a diverse pathology and can include developmental abnormalities, microcephaly and cancer predisposition.
  • Syndromes with impaired NHEJ also show dramatic immunological defects highlighting the role of NHEJ during development of the immunological system.
  • Syndromes related with defects in the repair of single‐strand breaks exhibit a pathology that is restricted to cerebellar ataxia and neurodegeneration.
  • The advancements in next‐generation sequencing will allow to associate more human disorders with defects in components of the DDR.

Keywords: genetic instability disorders; DNA damage repair; single‐strand break; double‐strand break; homologous recombination; nonhomologuos end‐joining

Figure 1. Single‐strand break repair. SSB repair can be divided into four steps: detection, end processing, gap filling and ligation. SSBs can arise by reactive oxygen species, during BER or after an abortive TOP1 activity; each would generate damaged 3′‐ and 5′‐termini that require different protein complexes to be processed into a normal 3′‐OH and 5′‐P termini in which XRCC1 acts as a scaffold to integrate the action of different proteins. The DNA end‐processing step is followed by gap filling. Usually polβ inserts the missing nucleotide, but in some cases the gap is bigger and also requires pol∂ and ϵ, as well as FEN1 and PARP (also involved in detection). Finally, depending on whether the gap to fill was short or long ligation would be done by LIG3 or LIG1, respectively (P, phosphate; αβ, unsaturated aldehyde; AMP; PG, phosphoglycolate; OH, hydroxyl; TOP1, TOP1 peptide).
Figure 2. Double‐strand break repair. There are two main DSB repair pathways: HR and NHEJ. DSB is sensed by PIKK kinases ATM and ATR. 5′‐End resection mediated by the regulation of CtIP and the action of MRN and several other nucleases exposes 3′‐end ssDNAs that is coated by RPA. RPA facilitates entrance of Rad52 and the subsequent assembly of a Rad51 nucleoprotein filament with the help of RAD51‐related proteins such as Brca2 or Rad54 that stimulates filament assembly. After identification of the identical sister chromatid sequence and reciprocal exchange, the intact double‐stranded copy is used as a template to properly heal the broken ends by DNA synthesis with the help of DNA polymerases and helicases. Finally, the resulting Holliday junctions are cleaved by resolvases. Alternatively, and in particular when a sister chromatid is not available, NHEJ is used as the main DSB repair pathway. NHEJ links the two ends of a DSB, without the use of a template. NHEJ uses, among other factors, the end‐binding Ku70/80 complex and DNA‐PKcs, which also recruits Artemis. Regardless of whether DNA ends are processed by nonprocessive DNA polymerases and helicases, NHEJ is completed via ligation by XRCC4/lig4 and XLF.


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Further Reading

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Chang HHY, Pannunzio NR, Adachi N and Lieber MR (2017) Non‐homologous DNA end joining and alternative pathways to double‐strand break repair. Nature Reviews Molecular Cell Biology 18: 495–506.

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O'Driscoll M (2012) Diseases associated with defective responses to DNA damage. Cold Spring Harbor Perspectives in Biology 4: a012773.

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Rass U, Ahel I and West SC (2007) Defective DNA repair and neurodegenerative disease. Cell 130 (6): 991–1004.

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García‐Muse, Tatiana, and Aguilera, Andrés(Jan 2018) DNA Strand Break Repair and Human Genetic Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021478.pub2]