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Structure‐based inhibitors of DNA repair
Author(s) -
Ellenberger Tome,
CotnerGohara Elizabeth,
Oberman Robert,
Kim InKwon,
Nolan William,
Tomkinson Alan,
Scharer Orlando D.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.526.1
Subject(s) - dna repair , dna damage , nucleotide excision repair , biology , genome instability , poly adp ribose polymerase , dna , base excision repair , dna mismatch repair , microbiology and biotechnology , endonuclease , ercc1 , polymerase , genetics
Damage‐specific DNA repair pathways are well understood as independent entities whereas little is known about how different repair activities are marshaled and integrated in a coordinated cellular response to DNA damage. Crosstalk between repair pathways, in the form of functional or physical interactions of constituent repair factors, can affect normal sensitivity to DNA damaging agents or modulate the consequences of genomic instability caused by the specific loss of a repair function. Tumor cells that are compromised in one DNA repair pathway may be particularly susceptible to killing by inhibitors of another DNA repair pathway, as evidenced by the sensitivity of BRCA1‐deficient tumors to inhibitors of PARP, the poly(ADP‐ribose) polymerase. We are developing small molecule inhibitors of protein interactions and enzymatic activities underlying nucleotide excision repair and DNA crosslink repair. Reversible, site‐specific inhibitors of DNA repair can serve as chemical genetic tools to explore functional connections between repair pathways and to validate candidate targets for the development of therapies that sensitize tumors to DNA damaging drugs. Our results with inhibitors of mammalian DNA ligases and the structure‐specific endonuclease ERCC1‐XPF will be discussed.