BRCA1-mediated repression of mutagenic end-joining of DNA double-strand breaks requires complex formation with BACH1.
BACH1 (BRCA1-associated C-terminal helicase 1), the product of the BRIP1 {BRCA1 [breast cancer 1, early onset]-interacting protein C-terminal helicase 1; also known as FANCJ [FA-J (Fanconi anaemia group J) protein]} gene mutated in Fanconi anaemia patients from complementation group J, has been implicated in DNA repair and damage signalling. BACH1 exerts DNA helicase activities and physically interacts with BRCA1 and MLH1 (mutL homologue 1), which differentially control DNA DSB (double-strand break) repair processes. The present study shows that BACH1 plays a role in both HR (homologous recombination) and MMEJ (microhomology-mediated non-homologous end-joining) and reveals discrete mechanisms underlying modulation of these pathways. Our results indicate that BACH1 stimulates HR, which depends on the integrity of the helicase domain. Disruption of the BRCA1-BACH1 complex through mutation of BACH1 compromised errorfree NHEJ (non-homologous end-joining) and accelerated error-prone MMEJ. Conversely, molecular changes in BACH1 abrogating MLH1 binding interfered neither with HR nor with MMEJ. Importantly, MMEJ is a mutagenic DSB repair pathway, which is derepressed in hereditary breast and ovarian carcinomas. Since BRCA1 and BACH1 mutations targeting the BRCA1-BACH1 interaction have been associated with breast cancer susceptibility, the results of the present study thus provide evidence for a novel role of BACH1 in tumour suppression.
Gynaecological Oncology Division, Department of Obstetrics and Gynaecology, University of Ulm, Prittwitzstrasse 43, D-89075 Ulm, Germany.
Lisa
L
Dohrn
Daniela
D
Salles
Simone Y
SY
Siehler
Julia
J
Kaufmann
Lisa
L
Wiesmüller
D000595:Amino Acid Sequence; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D001483:Base Sequence; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism* / Q000502:physiology; D002478:Cells, Cultured; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D051856:Fanconi Anemia Complementation Group Proteins / Q000378:metabolism* / Q000502:physiology; D005260:Female; D020022:Genetic Predisposition to Disease; D006367:HeLa Cells; D006801:Humans; D020014:K562 Cells; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000502:physiology; D011485:Protein Binding / Q000235:genetics / Q000502:physiology
C102108:BACH1 protein, human; D019313:BRCA1 Protein; D050976:Basic-Leucine Zipper Transcription Factors; D051856:Fanconi Anemia Complementation Group Proteins; D046912:Multiprotein Complexes