PMID- 10037723
OWN - NLM
STAT- MEDLINE
DCOM- 19990330
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 10
DP  - 1999 Mar 5
TI  - The interaction of the human MutL homologues in hereditary nonpolyposis colon 
      cancer.
PG  - 6336-41
AB  - Germline mutations in two human mismatch repair (MMR) genes, hMSH2 and hMLH1, 
      appear to account for approximately 70% of the common cancer susceptibility 
      syndrome hereditary nonpolyposis colorectal cancer (HNPCC). Although the hMLH1 
      protein has been found to copurify with another MMR protein hPMS2 as a 
      heterodimer, their function in MMR is unknown. In this study, we have identified 
      the physical interaction regions of both hMLH1 with hPMS2. We then examined the 
      effects of hMLH1 missense alterations found in HNPCC kindreds for their 
      interaction with hPMS2. Four of these missense alterations (L574P, K616Delta, 
      R659P, and A681T) displayed >95% reduction in binding to hPMS2. Two additional 
      missense alterations (K618A and K618T) displayed a >85% reduction in binding to 
      hPMS2, whereas three missense alterations (S44F, V506A, and E578G) displayed 
      25-65% reduction in binding to hPMS2. Interestingly, two HNPCC missense 
      alterations (Q542L and L582V) contained within the consensus interaction region 
      displayed no effect on interaction with hPMS2, suggesting that they may affect 
      other functions of hMLH1. These data confirm that functional deficiencies in the 
      interaction of hMLH1 with hPMS2 are associated with HNPCC as well as suggest that 
      other unknown functional alteration of the human MutL homologues may lead to 
      tumorigenesis in HNPCC kindreds.
FAU - Guerrette, S
AU  - Guerrette S
AD  - Genetics and Molecular Biology Program, Department of Microbiology and 
      Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, 
      Pennsylvania 19107, USA.
FAU - Acharya, S
AU  - Acharya S
FAU - Fishel, R
AU  - Fishel R
LA  - eng
GR  - R01 CA067007/CA/NCI NIH HHS/United States
GR  - CA56542/CA/NCI NIH HHS/United States
GR  - CA67007/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Bacterial Proteins)
RN  - 0 (Carrier Proteins)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Escherichia coli Proteins)
RN  - 0 (MLH1 protein, human)
RN  - 0 (MutL protein, E coli)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - EC 3.6.1.- (Adenosine Triphosphatases)
RN  - EC 3.6.1.3 (MSH2 protein, human)
RN  - EC 3.6.1.3 (MutL Protein Homolog 1)
RN  - EC 3.6.1.3 (MutL Proteins)
RN  - EC 3.6.1.3 (MutS Homolog 2 Protein)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing
MH  - *Adenosine Triphosphatases
MH  - Bacterial Proteins/*genetics
MH  - Carrier Proteins
MH  - Colorectal Neoplasms, Hereditary Nonpolyposis/*genetics
MH  - DNA Repair
MH  - *DNA-Binding Proteins
MH  - *Escherichia coli Proteins
MH  - *Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - MutL Protein Homolog 1
MH  - MutL Proteins
MH  - MutS Homolog 2 Protein
MH  - Mutation
MH  - Neoplasm Proteins/*genetics
MH  - Nuclear Proteins
MH  - Proto-Oncogene Proteins/*genetics
MH  - Sequence Homology, Nucleic Acid
EDAT- 1999/02/26 00:00
MHDA- 1999/02/26 00:01
CRDT- 1999/02/26 00:00
PHST- 1999/02/26 00:00 [pubmed]
PHST- 1999/02/26 00:01 [medline]
PHST- 1999/02/26 00:00 [entrez]
AID - S0021-9258(19)87592-0 [pii]
AID - 10.1074/jbc.274.10.6336 [doi]
PST - ppublish
SO  - J Biol Chem. 1999 Mar 5;274(10):6336-41. doi: 10.1074/jbc.274.10.6336.