Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:2.4.2.30 (
PARP
)
13,611
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The observation that BRCA1- and BRCA2-deficient cells are sensitive to inhibitors of poly(ADP-ribose) polymerase (
PARP
) has spurred the development of cancer therapies that use these inhibitors to target deficiencies in homologous recombination
1
. The cytotoxicity of
PARP
inhibitors depends on
PARP
trapping, the formation of non-covalent protein-DNA adducts composed of inhibited PARP1 bound to DNA lesions of unclear origins
1-4
. To address the nature of such lesions and the cellular consequences of
PARP
trapping, we undertook three CRISPR (clustered regularly interspersed palindromic repeats) screens to identify genes and pathways that mediate cellular resistance to olaparib, a clinically approved
PARP
inhibitor
1
. Here we present a high-confidence set of 73 genes, which when mutated cause increased sensitivity to
PARP
inhibitors. In addition to an expected enrichment for genes related to homologous recombination, we discovered that mutations in all three genes encoding
ribonuclease H2
sensitized cells to
PARP
inhibition. We establish that the underlying cause of the
PARP
-inhibitor hypersensitivity of cells deficient in
ribonuclease H2
is impaired ribonucleotide excision repair
5
. Embedded ribonucleotides, which are abundant in the genome of cells deficient in ribonucleotide excision repair, are substrates for cleavage by topoisomerase 1, resulting in
PARP
-trapping lesions that impede DNA replication and endanger genome integrity. We conclude that genomic ribonucleotides are a hitherto unappreciated source of
PARP
-trapping DNA lesions, and that the frequent deletion of RNASEH2B in metastatic prostate cancer and chronic lymphocytic leukaemia could provide an opportunity to exploit these findings therapeutically.
...
PMID:CRISPR screens identify genomic ribonucleotides as a source of PARP-trapping lesions. 3012 Mar 54
