Chemical Biology of                       Base Excision Repair   

Welcome to the David Lab! We use chemical approaches to investigate the fascinating area of DNA repair.  Damage to DNA can result in deleterious outcomes, such as cancer and aging; fortunately, most DNA damage is repaired by DNA repair enzymes.  Our laboratory focuses on the repair of damaged DNA bases which is mediated by the process of base excision repair.  The key enzymes in this pathway are the damage-specific DNA glycosylases that search through the vast amount of normal DNA to find subtle potentially mutagenic base modifications.  Our goals are to understand the molecular details associated with the recognition and repair of DNA damage, and how these features impact mutagenesis and carcinogenesis.  As chemical biologists interested in DNA repair, we use a variety of approaches, including enzymology, synthesis of modified substrates, spectroscopy, and cell biology.  Importantly, putting these approaches together in unique ways allows connections to be made between the molecular insight derived from our in vitro studies, and how these features impact repair in cells.  Ultimately this will reveal the critical features of the DNA repair process that prevents deleterious mutations leading to cancer, and how these processes may be manipulated for beneficial therapeutic purposes.


Learn More!

Our Latest Publication

MUTYH is a base excision repair (BER) protein that prevents mutations in DNA assocd. with 8-oxoguanine (OG) by catalyzing the removal of adenine from inappropriately formed OG:A base-pairs.  Germline mutations in the MUTYH gene are linked to colorectal polyposis and a high risk of colorectal cancer, a syndrome referred to as MUTYH-assocd. polyposis (MAP.  There are over 300 different MUTYH mutations assocd. with MAP and a large fraction of these gene changes code for missense MUTYH variants.  Herein, the adenine glycosylase activity, mismatch recognition properties, and interaction with relevant protein partners of human MUTYH and five MAP variants (R295C, P281L, Q324H, P502L, and R520Q) were examd.  P281L MUTYH was found to be severely compromised both in DNA binding and base excision activity, consistent with the location of this variation in the iron-sulfur cluster (FCL) DNA binding motif of MUTYH.  Both R295C and R520Q MUTYH were found to have low fractions of active enzyme, compromised affinity for damaged DNA, and reduced rates for adenine excision.  In contrast, both Q324H and P502L MUTYH function relatively similarly to WT MUTYH in both binding and glycosylase assays.  However, P502L and R520Q exhibited reduced affinity for PCNA (proliferation cell nuclear antigen), consistent with their location in the PCNA-binding motif of MUTYH.  Whereas, only Q324H, and not R295C, was found to have reduced affinity for Hus1 of the Rad9-Hus1-Rad1 complex, despite both being localized to the same region implicated for interaction with Hus1.  These results underscore the diversity of functional consequences due to MUTYH variants that may impact the progression of MAP.

Read Full Article

News From the David LaB

  • January 2015
    The David lab welcomes Chandrima Majumdar as a new grad student!
  • December 2014
    The Beal Lab was crushed by the David Lab competition at the annual Christmas party
  • September 2014
    The David lab welcomes Dr. Jonathan Ashby as a new postdoc! Good luck to Jongchan Yeo with starting his Postdoc. We will miss you!
  • June 2014
    Congratulations to Dr. Ryan Woods on his new job, Dr. JongChan Yeo on his new Postdoc and Dr. Patrick Rogers on his internship!
  • May 2014
    All three of the second years have made it through their QEs! Congratulations to Nicole Chaffee, Doug Banda, and Brittany Anderson on overcoming this huge milestone!
  • December 2013
    Congratulations to Dr. Alan Raetz for completing his Ph.D!

    Welcome Dr. Xiaoyan Ma to the David lab as our latest postdoc!

Recent Publications