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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

Okur MN, Mao B, Kimura R, Haraczy S, Fitzgerald T, Edwards-Hollingsworth K, Tian J, Osmani W, Croteau DL, Kelley MW, Bohr VA. Short-term NAD+ supplementation prevents hearing loss in mouse models of Cockayne syndrome. NPJ Aging Mech Dis. 2020 Jan 7;6:1. doi: 10.1038/s41514-019-0040-z. PMID: 31934345; PMCID: PMC6946667.

Lee JH, Demarest TG, Babbar M, Kim EW, Okur MN, De S, Croteau DL, Bohr VA. Cockayne syndrome group B deficiency reduces H3K9me3 chromatin remodeler SETDB1 and exacerbates cellular aging. Nucleic Acids Res. 2019 Sep 19;47(16):8548-8562. doi: 10.1093/nar/gkz568. PMID: 31276581; PMCID: PMC6895253.

Hou Y, Lautrup S, Cordonnier S, Wang Y, Croteau DL, Zavala E, Zhang Y, Moritoh K, O'Connell JF, Baptiste BA, Stevnsner TV, Mattson MP, Bohr VA. NAD+ supplementation normalizes key Alzheimer's features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency. Proc Natl Acad Sci U S A. 2018 Feb 20;115(8):E1876-E1885. doi: 10.1073/pnas.1718819115. Epub 2018 Feb 5. PMID: 29432159; PMCID: PMC5828618.

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. PMID: 27922005; PMCID: PMC5150655.