Activation of BRCA1/BRCA2-associated helicase BACH1 is required for timely progression through S phase.
BACH1 (also known as FANCJ and BRIP1) is a DNA helicase that directly interacts with the C-terminal BRCT repeat of the breast cancer susceptibility protein BRCA1. Previous biochemical and functional analyses have suggested a role for the BACH1 homolog in Caenorhabditis elegans during DNA replication. Here, we report the association of BACH1 with a distinct BRCA1/BRCA2-containing complex during the S phase of the cell cycle. Depletion of BACH1 or BRCA1 using small interfering RNAs results in delayed entry into the S phase of the cell cycle. Such timely progression through S phase requires the helicase activity of BACH1. Importantly, cells expressing a dominant negative mutation in BACH1 that results in a defective helicase displayed increased activation of DNA damage checkpoints and genomic instability. BACH1 helicase is silenced during the G(1) phase of the cell cycle and is activated through a dephosphorylation event as cells enter S phase. These results point to a critical role for BACH1 helicase activity not only in the timely progression through the S phase but also in maintaining genomic stability.
Kumaraswamy
Easwari
E
The Wistar Institute, Philadelphia, PA 19104, USA.
Shiekhattar
Ramin
R
D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism*; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage; D004789:Enzyme Activation; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D046912:Multiprotein Complexes; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D016196:S Phase / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
C102108:BACH1 protein, human; D019313:BRCA1 Protein; D024682:BRCA2 Protein; D050976:Basic-Leucine Zipper Transcription Factors; D002843:Chromatin; D051856:Fanconi Anemia Complementation Group Proteins; D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; C102449:BARD1 protein, human; D044767:Ubiquitin-Protein Ligases