PMID- 19047179
OWN - NLM
STAT- MEDLINE
DCOM- 20090116
LR  - 20240417
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 68
IP  - 23
DP  - 2008 Dec 1
TI  - Degradation of BRCA2 in alkyltransferase-mediated DNA repair and its clinical 
      implications.
PG  - 9973-81
LID - 10.1158/0008-5472.CAN-08-1179 [doi]
AB  - Germ-line mutations in BRCA2 have been linked to early-onset familial breast 
      cancer. BRCA2 is known to play a key role in repairing double-strand breaks. 
      Here, we describe the involvement of BRCA2 in O6-alkylguanine DNA 
      alkyltransferase (AGT)-mediated repair of O6-methylguanine adducts. We show that 
      BRCA2 physically associates and undergoes repair-mediated degradation with AGT. 
      In contrast, BRCA2 with a 29-amino-acid deletion in an evolutionarily conserved 
      domain does not bind to alkylated AGT; the two proteins are not degraded; and 
      mouse embryonic fibroblasts are specifically sensitive to alkylating agents that 
      result in O6-methylguanine adducts. We show that O6-benzylguanine (O6BG), a 
      nontoxic inhibitor of AGT, can also induce BRCA2 degradation. BRCA2 is a viable 
      target for cancer therapy because BRCA2-deficient cells are hypersensitive to 
      chemotherapeutic DNA-damaging agents. We show a marked effect of O6BG 
      pretreatment on cell sensitivity to cisplatin. We also show the efficacy of this 
      approach on a wide range of human tumor cell lines, which suggests that 
      chemosensitization of tumors by targeted degradation of BRCA2 may be an important 
      consideration when devising cancer therapeutics.
FAU - Philip, Subha
AU  - Philip S
AD  - Mouse Cancer Genetics Program, Center for Cancer Research, and Pathology 
      Histotechnology Laboratory, Science Applications International 
      Corporation-Frederick, Inc., National Cancer Institute at Frederick, Frederick, 
      Maryland 21702, USA.
FAU - Swaminathan, Srividya
AU  - Swaminathan S
FAU - Kuznetsov, Sergey G
AU  - Kuznetsov SG
FAU - Kanugula, Sreenivas
AU  - Kanugula S
FAU - Biswas, Kajal
AU  - Biswas K
FAU - Chang, Suhwan
AU  - Chang S
FAU - Loktionova, Natalia A
AU  - Loktionova NA
FAU - Haines, Diana C
AU  - Haines DC
FAU - Kaldis, Philipp
AU  - Kaldis P
FAU - Pegg, Anthony E
AU  - Pegg AE
FAU - Sharan, Shyam K
AU  - Sharan SK
LA  - eng
GR  - R01 CA018137/CA/NCI NIH HHS/United States
GR  - R37 CA018137/CA/NCI NIH HHS/United States
GR  - Z01 BC010387-08/ImNIH/Intramural NIH HHS/United States
GR  - CA018137/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Alkylating Agents)
RN  - 0 (BRCA2 Protein)
RN  - 0 (BRCA2 protein, mouse)
RN  - 01KC87F8FE (O(6)-benzylguanine)
RN  - 12H3O2UGSF (Methylnitronitrosoguanidine)
RN  - 5Z93L87A1R (Guanine)
RN  - 9B710FV2AE (O-(6)-methylguanine)
RN  - EC 2.1.1.63 (O(6)-Methylguanine-DNA Methyltransferase)
SB  - IM
MH  - Alkylating Agents
MH  - Amino Acid Sequence
MH  - Animals
MH  - BRCA2 Protein/genetics/*metabolism
MH  - DNA Repair/*physiology
MH  - Gene Deletion
MH  - Guanine/analogs & derivatives/metabolism/pharmacology
MH  - Humans
MH  - Methylnitronitrosoguanidine
MH  - Mice
MH  - Mice, Knockout
MH  - Mice, Transgenic
MH  - Molecular Sequence Data
MH  - O(6)-Methylguanine-DNA Methyltransferase/antagonists & inhibitors/*metabolism
PMC - PMC2729200
MID - NIHMS74134
EDAT- 2008/12/03 09:00
MHDA- 2009/01/17 09:00
PMCR- 2009/12/01
CRDT- 2008/12/03 09:00
PHST- 2008/12/03 09:00 [pubmed]
PHST- 2009/01/17 09:00 [medline]
PHST- 2008/12/03 09:00 [entrez]
PHST- 2009/12/01 00:00 [pmc-release]
AID - 68/23/9973 [pii]
AID - 10.1158/0008-5472.CAN-08-1179 [doi]
PST - ppublish
SO  - Cancer Res. 2008 Dec 1;68(23):9973-81. doi: 10.1158/0008-5472.CAN-08-1179.