Rad5-dependent DNA repair functions of the Saccharomyces cerevisiae FANCM protein homolog Mph1.
Interstrand cross-links (ICLs) covalently link complementary DNA strands, block DNA replication, and transcription and must be removed to allow cell survival. Several pathways, including the Fanconi anemia (FA) pathway, can faithfully repair ICLs and maintain genomic integrity; however, the precise mechanisms of most ICL repair processes remain enigmatic. In this study we genetically characterized a conserved yeast ICL repair pathway composed of the yeast homologs (Mph1, Chl1, Mhf1, Mhf2) of four FA proteins (FANCM, FANCJ, MHF1, MHF2). This pathway is epistatic with Rad5-mediated DNA damage bypass and distinct from the ICL repair pathways mediated by Rad18 and Pso2. In addition, consistent with the FANCM role in stabilizing ICL-stalled replication forks, we present evidence that Mph1 prevents ICL-stalled replication forks from collapsing into double-strand breaks. This unique repair function of Mph1 is specific for ICL damage and does not extend to other types of damage. These studies reveal the functional conservation of the FA pathway and validate the yeast model for future studies to further elucidate the mechanism of the FA pathway.
Genome Instability Section, Genetics, and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
Danielle L
DL
Daee
Elisa
E
Ferrari
Simonne
S
Longerich
Xiao-feng
XF
Zheng
Xiaoyu
X
Xue
Dana
D
Branzei
Patrick
P
Sung
Kyungjae
K
Myung
D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000502:physiology*; D004265:DNA Helicases / Q000235:genetics / Q000502:physiology*; D004260:DNA Repair / Q000502:physiology*; D016521:Electrophoresis, Gel, Pulsed-Field; D005434:Flow Cytometry; D006801:Humans; D009154:Mutation; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000502:physiology*
D029701:Saccharomyces cerevisiae Proteins; C518295:FANCM protein, human; C491240:MPH1 protein, S cerevisiae; C076225:RAD5 protein, S cerevisiae; D004265:DNA Helicases; D053487:DEAD-box RNA Helicases