Elsevier

DNA Repair

Volume 12, Issue 8, August 2013, Pages 558-567
DNA Repair

DNA strand break repair and neurodegeneration

https://doi.org/10.1016/j.dnarep.2013.04.008Get rights and content

Abstract

A number of DNA repair disorders are known to cause neurological problems. These disorders can be broadly characterised into early developmental, mid-to-late developmental or progressive. The exact developmental processes that are affected can influence disease pathology, with symptoms ranging from early embryonic lethality to late-onset ataxia. The category these diseases belong to depends on the frequency of lesions arising in the brain, the role of the defective repair pathway, and the nature of the mutation within the patient. Using observations from patients and transgenic mice, we discuss the importance of double strand break repair during neuroprogenitor proliferation and brain development and the repair of single stranded lesions in neuronal function and maintenance.

Introduction

The genome is constantly under attack from endogenous and exogenous genotoxic agents, and also possesses an inherent level of instability [1]. Breaks can arise in one or both DNA strands, and chemical adducts or crosslinks can arise on or between DNA bases [2], [3], [4]. In addition, the breakage and repair of cellular DNA is also a necessary part of several cellular processes critical for cellular growth and proliferation and for organismal development. Genome stability and maintenance requires a number of overlapping biochemical pathways involving many different proteins, clustered into specific DNA repair pathways. Loss of function of these proteins can lead to a variety of disorders, with pathologies including growth and developmental defects, immunodeficiency, cancer, neurodegeneration and ageing [5], [6], [7]. The association of DNA repair defects with both elevated predisposition to cancer and to increased rates of neurodegeneration and ageing, sometimes in the same genetic disease, is particularly intriguing, because cancer is a disease of excessive cell growth and survival, whereas neurodegeneration is a disease of excessive cell dysfunction and death. Opposite cellular end points can thus arise from defects in common or related processes [8]. In this review we focus on DNA damage defective diseases associated with neurological dysfunction, and attempt to rationalise the differences in underlying molecular defects between developmental and neurodegenerative pathologies.

Section snippets

Brain development

Embryonic development involves waves of rapid cell division throughout the developing embryo, followed by complex periods of migration and differentiation (Fig. 1) [9]. During this time there is a requirement for rapid and efficient mechanisms to fix transcription- and replication-associated DNA breaks as well as naturally occurring oxidative breaks. Failure to repair these breaks may lead to the accumulation of damage and cell death, resulting in neuronal loss at different stages of

Double strand break repair and neurogenesis

Double strand break repair (DSBR) involves two distinct pathways (Fig. 2) [16]: during G1 and early S-phase, the dominant repair pathway involves the processing and ligation of non-homologous DNA ends (non-homologous end joining; NHEJ). The principal components of NHEJ are DNA-dependent protein kinase (DNA-PK), XRCC4, DNA ligase 4 (Lig4) and XLF/Cernunnos. Damaged DNA termini are processed primarily by PNKP, TDP2, Artemis, aprataxin, or by one of several nucleases, which prepare the DNA ends

Progressive neurodegeneration and cerebellar ataxia

Whilst DSBs are severe lesions that impact greatly on proliferating and differentiating cells, and consequently on neurodevelopment, these lesions are relatively rare. In contrast, lesions on a single strand of DNA, and in particular single-strand breaks (SSBs), arise 3 orders of magnitude more frequently. Single-strand lesions are normally repaired rapidly by the SSBR and TC-NER pathways (Fig. 4), but if these pathways are defective, long-lived single-strand lesions can trigger cell death by

Conclusion

Recent data from transgenic models has enabled us to resolve the overlapping neurological phenotypes in DNA repair disorders. As illustrated in Fig. 1, these disorders can be categorised into early developmental (embryonic lethality) mid-to-late developmental (microcephaly) or post-developmental (neurodegenerative). Broadly-speaking, these categories are defined by the repair pathway that is defective, with a requirement for HR particularly evident during early development, NHEJ during late

Conflict of interest statement

None.

References (156)

  • D. Durocher et al.

    DNA-PK, ATM and ATR as sensors of DNA damage: variations on a theme?

    Curr. Opin. Cell Biol.

    (2001)
  • K.M. Frank et al.

    DNA ligase IV deficiency in mice leads to defective neurogenesis and embryonic lethality via the p53 pathway

    Mol. Cell

    (2000)
  • C. Barlow et al.

    Atm-deficient mice: a paradigm of ataxia telangiectasia

    Cell

    (1996)
  • K.M. Sleeth et al.

    RPA mediates recombination repair during replication stress and is displaced from DNA by checkpoint signalling in human cells

    J. Mol. Biol.

    (2007)
  • J. Goodship et al.

    Autozygosity mapping of a Seckel syndrome locus to chromosome 3q22.1-q24

    Am. J. Hum. Genet.

    (2000)
  • A. de Klein et al.

    Targeted disruption of the cell-cycle checkpoint gene ATR leads to early embryonic lethality in mice

    Curr. Biol.

    (2000)
  • R.S. Williams et al.

    A nanomachine for making ends meet: MRN is a flexing scaffold for the repair of DNA double-strand breaks

    Mol. Cell

    (2005)
  • T.T. Paull et al.

    The 3′ to 5′ exonuclease activity of Mre 11 facilitates repair of DNA double-strand breaks

    Mol. Cell

    (1998)
  • R. Varon et al.

    Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome

    Cell

    (1998)
  • G.S. Stewart et al.

    The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder

    Cell

    (1999)
  • R. Waltes et al.

    Human RAD50 deficiency in a Nijmegen breakage syndrome-like disorder

    Am. J. Hum. Genet.

    (2009)
  • J. Zhu et al.

    Targeted disruption of the Nijmegen breakage syndrome gene NBS1 leads to early embryonic lethality in mice

    Curr. Biol.

    (2001)
  • J. Buis et al.

    Mre11 nuclease activity has essential roles in DNA repair and genomic stability distinct from ATM activation

    Cell

    (2008)
  • B.R. Williams et al.

    A murine model of Nijmegen breakage syndrome

    Curr. Biol.

    (2002)
  • J.W. Theunissen et al.

    Checkpoint failure and chromosomal instability without lymphomagenesis in Mre11(ATLD1/ATLD1) mice

    Mol. Cell

    (2003)
  • A.R. Lehmann

    DNA repair-deficient diseases, xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy

    Biochimie

    (2003)
  • K. Sugasawa et al.

    Xeroderma pigmentosum group C protein complex is the initiator of global genome nucleotide excision repair

    Mol. Cell

    (1998)
  • V.A. Bohr et al.

    DNA repair in an active gene: removal of pyrimidine dimers from the DHFR gene of CHO cells is much more efficient than in the genome overall

    Cell

    (1985)
  • I. Mellon et al.

    Selective removal of transcription-blocking DNA damage from the transcribed strand of the mammalian DHFR gene

    Cell

    (1987)
  • D. Mu et al.

    Model for XPC-independent transcription-coupled repair of pyrimidine dimers in humans

    J. Biol. Chem.

    (1997)
  • C.L. Licht et al.

    Cockayne syndrome group B cellular and biochemical functions

    Am. J. Hum. Genet.

    (2003)
  • K.A. Henning et al.

    The Cockayne syndrome group A gene encodes a WD repeat protein that interacts with CSB protein and a subunit of RNA polymerase II TFIIH

    Cell

    (1995)
  • D.L. Mallery et al.

    Molecular analysis of mutations in the CSB (ERCC6) gene in patients with Cockayne syndrome

    Am. J. Hum. Genet.

    (1998)
  • G.T. van der Horst et al.

    Defective transcription-coupled repair in Cockayne syndrome B mice is associated with skin cancer predisposition

    Cell

    (1997)
  • T. Lindahl

    Instability and decay of the primary structure of DNA

    Nature

    (1993)
  • J. Rouse et al.

    Interfaces between the detection, signaling, and repair of DNA damage

    Science

    (2002)
  • J.H. Hoeijmakers

    Genome maintenance mechanisms for preventing cancer

    Nature

    (2001)
  • M. O’Driscoll et al.

    The role of double-strand break repair—insights from human genetics

    Nat. Rev. Genet.

    (2006)
  • P.J. McKinnon et al.

    DNA strand break repair and human genetic disease

    Annu. Rev. Genomics Hum. Genet.

    (2007)
  • J.H. Hoeijmakers

    DNA damage, aging, and cancer

    N. Engl. J. Med.

    (2009)
  • L.G. Morris et al.

    Genetic determinants at the interface of cancer and neurodegenerative disease

    Oncogene

    (2010)
  • N. Zecevic et al.

    Interneurons in the developing human neocortex

    Dev. Neurobiol.

    (2011)
  • K. Letinic et al.

    Origin of GABAergic neurons in the human neocortex

    Nature

    (2002)
  • N. Sanai et al.

    Corridors of migrating neurons in the human brain and their decline during infancy

    Nature

    (2011)
  • N. Bayatti et al.

    A molecular neuroanatomical study of the developing human neocortex from 8 to 17 postconceptional weeks revealing the early differentiation of the subplate and subventricular zone

    Cereb. Cortex

    (2008)
  • N. Zecevic et al.

    Contributions of cortical subventricular zone to the development of the human cerebral cortex

    J. Comp. Neurol.

    (2005)
  • S.P. Jackson

    Sensing and repairing DNA double-strand breaks

    Carcinogenesis

    (2002)
  • M.R. Lieber

    The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway

    Annu. Rev. Biochem.

    (2010)
  • E. Weterings et al.

    The endless tale of non-homologous end-joining

    Cell Res.

    (2008)
  • M.E. Moynahan et al.

    Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis

    Nat. Rev. Mol. Cell Biol.

    (2010)
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