Using molecular, biochemical and structural approaches, over the past many years, we have broadly contributed to defining how specific human BER proteins recognize and process target lesions, as well as coordinate with other components of the pathway. This research has centered largely on apurinic/apyrimidinic endonuclease 1 (APE1), the major mammalian protein for repairing abasic sites in DNA, and x-ray cross-complementing 1 (XRCC1), a non-enzymatic scaffold protein that facilitates the efficient execution of single-strand break (SSB) repair. Some of our most recent work has described that (i) XRCC1 coordinates disparate responses and multi-protein repair complexes that are dependent on the nature and context of the DNA damage;(ii) the different regions of XRCC1 play distinct roles in coordinating repair complex assembly and the population variants Arg280His and Arg399Gln exhibit reduced stability at DNA damage foci, suggesting that they may represent disease susceptibility factors;and (iii) certain BER components can interfere with the processing of DNA interstrand crosslinks (ICLs), which are created both by natural events and by exposure to certain chemotherapeutic agents. Our results have implications for how BER proteins may affect disease susceptibility and therapeutic agent responsiveness. APE1 is the major mammalian enzyme responsible for the repair of abasic sites in DNA, and has functions in SSB repair and other cellular processes, including transcriptional regulation. We are in the process of establishing genetically modified cell lines to dissect out the precise contribution of each proposed function of APE1 (i.e. its nuclease activity, redox regulatory role, etc.) in cell growth/viability, genome maintenance, and protection against DNA-damaging agents. In addition, we are developing small molecule probes to complement the proposed genetic experiments to define the biological roles of specific APE1 activities. The underlying hypothesis is that APE1, and BER more generally, plays a critical role in dictating cellular responsiveness to genotoxic insults and susceptibility to disease manifestation, particularly in the face of certain environmental exposure(s). Defining which of the many reported functions of APE1 are critical to normal cellular activity is a key step towards understanding the potential relationship of the protein to the aging process and disease risk. DNA ICLs can arise from reactions with endogenous chemicals, such as the lipid peroxidation product malondialdehyde, as well as from exposure to a variety of clinical anti-cancer agents, such as bifunctional alkylators. Recent studies suggest a role for BER in the processing of these highly toxic DNA intermediates, which are absolute blocks to transcription and replication, and thus, lethal adducts. We are continuing experiments using developed strategies, e.g. laser microirradiation coupled with high resolution confocal microscopy, to define the molecular involvement of specific repair factors in ICL removal. Elucidating the roles of DNA repair proteins in ICL resolution may reveal new targets relevant to anti-cancer treatment paradigms.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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National Institute on Aging
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Hinz, John M; Mao, Peng; McNeill, Daniel R et al. (2015) Reduced Nuclease Activity of Apurinic/Apyrimidinic Endonuclease (APE1) Variants on Nucleosomes: IDENTIFICATION OF ACCESS RESIDUES. J Biol Chem 290:21067-75
Li, Mengxia; Völker, Jens; Breslauer, Kenneth J et al. (2014) APE1 incision activity at abasic sites in tandem repeat sequences. J Mol Biol 426:2183-98
Poletto, Mattia; Lirussi, Lisa; Wilson 3rd, David M et al. (2014) Nucleophosmin modulates stability, activity, and nucleolar accumulation of base excision repair proteins. Mol Biol Cell 25:1641-52
McNeill, Daniel R; Paramasivam, Manikandan; Baldwin, Jakita et al. (2013) NEIL1 responds and binds to psoralen-induced DNA interstrand crosslinks. J Biol Chem 288:12426-36
Li, Mengxia; Wilson 3rd, David M (2013) Human Apurinic/Apyrimidinic Endonuclease 1. Antioxid Redox Signal :
Hanssen-Bauer, Audun; Solvang-Garten, Karin; Gilljam, Karin Margaretha et al. (2012) The region of XRCC1 which harbours the three most common nonsynonymous polymorphic variants, is essential for the scaffolding function of XRCC1. DNA Repair (Amst) 11:357-66
Tadokoro, Takashi; Ramamoorthy, Mahesh; Popuri, Venkateswarlu et al. (2012) Human RECQL5 participates in the removal of endogenous DNA damage. Mol Biol Cell 23:4273-85
Della-Maria, Julie; Hegde, Muralidhar L; McNeill, Daniel R et al. (2012) The interaction between polynucleotide kinase phosphatase and the DNA repair protein XRCC1 is critical for repair of DNA alkylation damage and stable association at DNA damage sites. J Biol Chem 287:39233-44
Berquist, Brian R; Wilson 3rd, David M (2012) Pathways for repairing and tolerating the spectrum of oxidative DNA lesions. Cancer Lett 327:61-72
Kim, Yun-Jeong; Kim, Daemyung; Illuzzi, Jennifer L et al. (2011) S-glutathionylation of cysteine 99 in the APE1 protein impairs abasic endonuclease activity. J Mol Biol 414:313-26

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