Ben Van Houten, Ph.D.
University of Pittsburgh
R01ES019566, R01ES028686, R33ES025606, T32ES007059
A team of NIEHS grantees working wtih an NIEHS in-house researcher found that a protein that helps safeguard against DNA damage from the sun is also useful for finding general DNA damage and overseeing its repair. The protein, ultraviolet-damaged DNA-binding protein (UV-DDB), is a known key protein in human global nucleotide excision repair, which is an important mechanism for removing DNA damage caused by UV light. This study showed that the protein also senses damage and plays a key role in base excision repair, another important DNA repair pathway.
The research team developed a new method to track enzymes involved in DNA repair in 3D using real-time, single molecule imaging. They induced oxidative stress in DNA and observed that UV-DDB was rapidly recruited to sites containing specific DNA damage. UV-DDB also stimulated repair activity by forming complexes with enzymes that are essential in base excision repair. One important rate-limiting step during base excision repair is access to DNA damage in tightly packed chromatin in the nucleus. They found that UV-DDB can find damage on DNA buried in chromosomes and help DNA repair molecules access those sites.
To further explore the role of UV-DDB in base excision repair, researchers depleted UV-DDB from living cells and compared them to cells with UV-DDB. When they inflicted damage usually repaired by base excision on both types of cells, they found that loss of UV-DDB sensitized cells to the DNA damage. According to the authors, this study provides novel insight into a new damage sensor role for UV-DDB in base excision repair.
Citation: Jang S, Kumar N, Beckwitt EC, Kong M, Fouquerel E, Rapic-Otrin V, Prasad R, Watkins SC, Khuu C, Majumdar C, David SS, Wilson SH, Bruchez MP, Opresko PL, Van Houten B. 2019. Damage sensor role of UV-DDB during base excision repair. Nat Struct Mol Biol 26(8):695–703.