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Section on DNA Repair

Vilhelm A Bohr, MD, Ph.D., Chief

Our laboratory has four broad sections: RecQ helicases, base excision repair (BER), Cockayne syndrome and neurodegeneration. DNA damage accumulates during life and is thought to contribute to aging and genomic instability. Therefore, defining those proteins and pathways that maintain genomic stability is critical in preventing aging and age-related degeneration. The five human RecQ proteins participate in DNA repair and genomic stability. We are defining what role RecQ proteins play in DNA double-strand break repair including: homologous recombination, non-homologous end joining, alternative non-homologous end joining and replication repair. Oxidative lesions are removed from DNA primarily via the BER pathway. Oxidative DNA damage is implicated in brain aging, neurodegeneration and neurological diseases. We are investigating the importance of BER in Alzheimer's disease and olfactory function. Cockayne syndrome (CS) is a devastating autosomal recessive disease characterized by neurodegeneration, cachexia, and accelerated aging. Based on the signs and symptoms seen in Cockayne Syndrome (CS) and other DNA repair deficient disorders like Ataxia Telangiectasia (AT) and Xeroderma Pigmentosum group A (XPA), we classified these disorders as likely having a mitochondrial component. We have identified a mitochondrial stress phenotype in these disorders and it is described more below in the description of the Unit on Oxidative DNA Damage Processing and Mitochondrial Functions.  Together we seek to understand how DNA repair deficiencies contribute to cellular dysfunction, neurodegeneration, and aging.

Portfolio/Research Areas

  • DNA Damage Response
  • DNA repair
  • Double Strand Break Repair
  • Base Excision Repair
  • Alzheimer’s Disease
  • Mitochondrial Metabolism
  • Autophagy/Mitophagy
  • Premature Aging Syndromes
  • Werner’s Syndrome
  • Cockayne Syndrome
  • Ataxia Telangiectasia
  • Rothmund-Thomson Syndrome

Findings and Publications

Misiak M, Vergara Greeno R, Baptiste BA, Sykora P, Liu D, Cordonnier S, Fang EF, Croteau DL, Mattson MP, Bohr VA. DNA polymerase β decrement triggers death of olfactory bulb cells and impairs olfaction in a mouse model of Alzheimer's disease. Aging Cell. 2017 Feb;16(1):162-172. doi: 10.1111/acel.12541. PubMed PMID: 27686631; PubMed Central PMCID: PMC5242308.

Sykora P, Misiak M, Wang Y, Ghosh S, Leandro GS, Liu D, Tian J, Baptiste BA, Cong WN, Brenerman BM, Fang E, Becker KG, Hamilton RJ, Chigurupati S, Zhang Y, Egan JM, Croteau DL, Wilson DM 3rd, Mattson MP, Bohr VA. DNA polymerase β deficiency leads to neurodegeneration and exacerbates Alzheimer disease phenotypes. Nucleic Acids Res. 2015 Jan;43(2):943-59. doi: 10.1093/nar/gku1356. PubMed PMID: 25552414; PubMed Central PMCID: PMC4333403.

Shamanna RA, Lu H, de Freitas JK, Tian J, Croteau DL, Bohr VA. WRN regulates pathway choice between classical and alternative non-homologous end joining. Nat Commun. 2016 Dec 6;7:13785. doi: 10.1038/ncomms13785. PubMed PMID: 27922005; PubMed Central PMCID: PMC5150655.

Lu H, Shamanna RA, Keijzers G, Anand R, Rasmussen LJ, Cejka P, Croteau DL, Bohr VA. RECQL4 Promotes DNA End Resection in Repair of DNA Double-Strand Breaks. Cell Rep. 2016 Jun 28;16(1):161-73. doi: 10.1016/j.celrep.2016.05.079. PubMed PMID: 27320928.

Khadka P, Croteau DL, Bohr VA. RECQL5 has unique strand annealing properties relative to the other human RecQ helicase proteins. DNA Repair (Amst). 2016 Jan;37:53-66. doi: 10.1016/j.dnarep.2015.11.005. PubMed PMID: 26717024.