The human mismatch recognition complex hMSH2-hMSH6 functions as a novel molecular switch

被引:304
作者
Gradia, S [1 ]
Acharya, S [1 ]
Fishel, R [1 ]
机构
[1] Thomas Jefferson Univ, Kimmel Canc Ctr, Genet & Mol Biol Program, Dept Microbiol & Immunol, Philadelphia, PA 19107 USA
关键词
D O I
10.1016/S0092-8674(00)80490-0
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The mechanism of DNA mismatch repair has been modeled upon biochemical studies of the E. coli DNA adenine methylation-instructed pathway where the initial recognition of mismatched nucleotides is performed by the MutS protein. MutS homologs (MSH) have been identified based on a highly conserved region containing a Walker-A adenine nucleotide binding motif. Here we show that adenine nucleotide binding and hydrolysis by the human mismatch recognition complex hMSH2-hMSH6 functions as a novel molecular switch. The hMSH2-hMSH6 complex is ON (binds mismatched nucleotides) in the ADP-bound form and OFF in the ATP-bound form. These results suggest a new model for the function of MutS proteins during mismatch repair in which the switch determines the timing of downstream events.
引用
收藏
页码:995 / 1005
页数:11
相关论文
共 49 条
[31]  
MODRICH P, 1989, J BIOL CHEM, V264, P6597
[32]   Strand-specific mismatch repair in mammalian cells [J].
Modrich, P .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (40) :24727-24730
[33]   Mismatch repair in replication fidelity, genetic recombination, and cancer biology [J].
Modrich, P ;
Lahue, R .
ANNUAL REVIEW OF BIOCHEMISTRY, 1996, 65 :101-133
[34]   MUTATIONS OF 2 PMS HOMOLOGS IN HEREDITARY NONPOLYPOSIS COLON-CANCER [J].
NICOLAIDES, NC ;
PAPADOPOULOS, N ;
LIU, B ;
WEI, YF ;
CARTER, KC ;
RUBEN, SM ;
ROSEN, CA ;
HASELTINE, WA ;
FLEISCHMANN, RD ;
FRASER, CM ;
ADAMS, MD ;
VENTER, JC ;
DUNLOP, MG ;
HAMILTON, SR ;
PETERSEN, GM ;
DELACHAPELLE, A ;
VOGELSTEIN, B ;
KINZLER, KW .
NATURE, 1994, 371 (6492) :75-80
[35]   hMutS beta, a heterodimer of hMSH2 and hMSH3, binds to insertion/deletion leaps in DNA [J].
Palombo, F ;
Iaccarino, I ;
Nakajima, E ;
Ikejima, M ;
Shimada, T ;
Jiricny, J .
CURRENT BIOLOGY, 1996, 6 (09) :1181-1184
[36]   MLH1, PMS1, AND MSH2 INTERACTIONS DURING THE INITIATION OF DNA MISMATCH REPAIR IN YEAST [J].
PROLLA, TA ;
PANG, QS ;
ALANI, E ;
KOLODNER, RD ;
LISKAY, RM .
SCIENCE, 1994, 265 (5175) :1091-1093
[37]   GUANINE-NUCLEOTIDE EXCHANGE FACTORS - ACTIVATORS OF THE RAS SUPERFAMILY OF PROTEINS [J].
QUILLIAM, LA ;
KHOSRAVIFAR, R ;
HUFF, SY ;
DER, CJ .
BIOESSAYS, 1995, 17 (05) :395-404
[38]   Mutation of MSH3 in endometrial cancer and evidence for its functional role in heteroduplex repair [J].
Risinger, JI ;
Umar, A ;
Boyd, J ;
Berchuck, A ;
Kunkel, TA ;
Barrett, JC .
NATURE GENETICS, 1996, 14 (01) :102-105
[39]   SIGNAL TRANSDUCTION BY GUANINE-NUCLEOTIDE BINDING-PROTEINS [J].
SPIEGEL, AM .
MOLECULAR AND CELLULAR ENDOCRINOLOGY, 1987, 49 (01) :1-16
[40]   ESCHERICHIA-COLI MUTS-ENCODED PROTEIN BINDS TO MISMATCHED DNA-BASE PAIRS [J].
SU, SS ;
MODRICH, P .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1986, 83 (14) :5057-5061