|
|
|
|
Dominant Mutations in S. cerevisiae PMS1 Identify the Mlh1-Pms1 Endonuclease Active Site and an Exonuclease 1-Independent Mismatch Repair Pathway
|
|
|
|
|
|
|
|
نویسنده
|
smith c.e. ,mendillo m.l. ,bowen n. ,hombauer h. ,campbell c.s. ,desai a. ,putnam c.d. ,kolodner r.d.
|
|
منبع
|
plos genetics - 2013 - دوره : 9 - شماره : 10
|
|
چکیده
|
Lynch syndrome (hereditary nonpolypsis colorectal cancer or hnpcc) is a common cancer predisposition syndrome. predisposition to cancer in this syndrome results from increased accumulation of mutations due to defective mismatch repair (mmr) caused by a mutation in one of the mismatch repair genes mlh1,msh2,msh6 or pms2/scpms1. to better understand the function of mlh1-pms1 in mmr,we used saccharomyces cerevisiae to identify six pms1 mutations (pms1-g683e,pms1-c817r,pms1-c848s,pms1-h850r,pms1-h703a and pms1-e707a) that were weakly dominant in wild-type cells,which surprisingly caused a strong mmr defect when present on low copy plasmids in an exo1δ mutant. molecular modeling showed these mutations caused amino acid substitutions in the metal coordination pocket of the pms1 endonuclease active site and biochemical studies showed that they inactivated the endonuclease activity. this model of mlh1-pms1 suggested that the mlh1-ferc motif contributes to the endonuclease active site. consistent with this,the mlh1-e767stp mutation caused both mmr and endonuclease defects similar to those caused by the dominant pms1 mutations whereas mutations affecting the predicted metal coordinating residue mlh1-c769 had no effect. these studies establish that the mlh1-pms1 endonuclease is required for mmr in a previously uncharacterized exo1-independent mmr pathway. © 2013 smith et al.
|
|
|
|
|
آدرس
|
ludwig institute for cancer research,university of california school of medicine,san diego,la jolla,ca, United States, ludwig institute for cancer research,university of california school of medicine,san diego,la jolla,ca,united states,whitehead institute for biomedical research,cambridge,ma, United States, ludwig institute for cancer research,university of california school of medicine,san diego,la jolla,ca, United States, ludwig institute for cancer research,university of california school of medicine,san diego,la jolla,ca,united states,german cancer research center,dkfz,heidelberg, Germany, ludwig institute for cancer research,university of california school of medicine,san diego,la jolla,ca, United States, ludwig institute for cancer research,university of california school of medicine,san diego,la jolla,ca,united states,department of cellular and molecular medicine and moores-ucsd cancer center,university of california school of medicine,san diego,la jolla,ca, United States, ludwig institute for cancer research,university of california school of medicine,san diego,la jolla,ca,united states,department of medicine,university of california school of medicine,san diego,la jolla,ca, United States, ludwig institute for cancer research,university of california school of medicine,san diego,la jolla,ca,united states,department of cellular and molecular medicine and moores-ucsd cancer center,university of california school of medicine,san diego,la jolla,ca,united states,department of medicine,university of california school of medicine,san diego,la jolla,ca,united states,institute of genomic medicine,university of california school of medicine,san diego,la jolla,ca, United States
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Authors
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|