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DNA mismatch repair gene MSH6 implicated in determining age at natural menopause.

ABSTRACT: The length of female reproductive lifespan is associated with multiple adverse outcomes, including breast cancer, cardiovascular disease and infertility. The biological processes that govern the timing of the beginning and end of reproductive life are not well understood. Genetic variants are known to contribute to ?50% of the variation in both age at menarche and menopause, but to date the known genes explain <15% of the genetic component. We have used genome-wide association in a bivariate meta-analysis of both traits to identify genes involved in determining reproductive lifespan. We observed significant genetic correlation between the two traits using genome-wide complex trait analysis. However, we found no robust statistical evidence for individual variants with an effect on both traits. A novel association with age at menopause was detected for a variant rs1800932 in the mismatch repair gene MSH6 (P = 1.9 × 10(-9)), which was also associated with altered expression levels of MSH6 mRNA in multiple tissues. This study contributes to the growing evidence that DNA repair processes play a key role in ovarian ageing and could be an important therapeutic target for infertility.

SUBMITTER: Perry JR

PROVIDER: S-EPMC3976329 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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DNA mismatch repair gene MSH6 implicated in determining age at natural menopause.

Perry John R B JR Hsu Yi-Hsiang YH Chasman Daniel I DI Johnson Andrew D AD Elks Cathy C Albrecht Eva E Andrulis Irene L IL Beesley Jonathan J Berenson Gerald S GS Bergmann Sven S Bojesen Stig E SE Bolla Manjeet K MK Brown Judith J Buring Julie E JE Campbell Harry H Chang-Claude Jenny J Chenevix-Trench Georgia G Corre Tanguy T Couch Fergus J FJ Cox Angela A Czene Kamila K D'adamo Adamo Pio AP Davies Gail G Deary Ian J IJ Dennis Joe J Easton Douglas F DF Engelhardt Ellen G EG Eriksson Johan G JG Esko Tõnu T Fasching Peter A PA Figueroa Jonine D JD Flyger Henrik H Fraser Abigail A Garcia-Closas Montse M Gasparini Paolo P Gieger Christian C Giles Graham G Guenel Pascal P Hägg Sara S Hall Per P Hayward Caroline C Hopper John J Ingelsson Erik E Kardia Sharon L R SL Kasiman Katherine K Knight Julia A JA Lahti Jari J Lawlor Debbie A DA Magnusson Patrik K E PK Margolin Sara S Marsh Julie A JA Metspalu Andres A Olson Janet E JE Pennell Craig E CE Polasek Ozren O Rahman Iffat I Ridker Paul M PM Robino Antonietta A Rudan Igor I Rudolph Anja A Salumets Andres A Schmidt Marjanka K MK Schoemaker Minouk J MJ Smith Erin N EN Smith Jennifer A JA Southey Melissa M Stöckl Doris D Swerdlow Anthony J AJ Thompson Deborah J DJ Truong Therese T Ulivi Sheila S Waldenberger Melanie M Wang Qin Q Wild Sarah S Wilson James F JF Wright Alan F AF Zgaga Lina L Ong Ken K KK Murabito Joanne M JM Karasik David D Murray Anna A

Human molecular genetics 20131219 9

The length of female reproductive lifespan is associated with multiple adverse outcomes, including breast cancer, cardiovascular disease and infertility. The biological processes that govern the timing of the beginning and end of reproductive life are not well understood. Genetic variants are known to contribute to ∼50% of the variation in both age at menarche and menopause, but to date the known genes explain <15% of the genetic component. We have used genome-wide association in a bivariate met ...[more]

PMID: 24357391

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Project description:DNA mismatch repair (MMR) is an important postreplication process that eliminates mispaired or unpaired nucleotides to ensure genomic replication fidelity. In humans, Msh2-Msh6 and Msh2-Msh3 are the two mismatch repair initiation factors that recognize DNA lesions. While X-ray crystal structures exist for these proteins in complex with DNA lesions, little is known about their structures during the initial search along nonspecific double-stranded DNA, because they are short-lived and difficult to determine experimentally. In this study, various computational approaches were used to sidestep these difficulties. All-atom and coarse-grained simulations based on the crystal structures of Msh2-Msh3 and Msh2-Msh6 showed no translation along the DNA, suggesting that the initial search conformation differs from the lesion-bound crystal structure. We modeled probable search-mode structures of MSH proteins and showed, using coarse-grained molecular dynamics simulations, that they can perform rotation-coupled diffusion on DNA, which is a suitable and efficient search mechanism for their function and one predicted earlier by fluorescence resonance energy transfer and fluorescence microscopy studies. This search mechanism is implemented by electrostatic interactions among the mismatch-binding domain (MBD), the clamp domains, and the DNA backbone. During simulations, their diffusion rate did not change significantly with an increasing salt concentration, which is consistent with observations from experimental studies. When the gap between their DNA-binding clamps was increased, Msh2-Msh3 diffused mostly via the clamp domains while Msh2-Msh6 still diffused using the MBD, reproducing the experimentally measured lower diffusion coefficient of Msh2-Msh6. Interestingly, Msh2-Msh3 was capable of dissociating from the DNA, whereas Msh2-Msh6 always diffused on the DNA duplex. This is consistent with the experimental observation that Msh2-Msh3, unlike Msh2-Msh6, can overcome obstacles such as nucleosomes. Our models provide a molecular picture of the different mismatch search mechanisms undertaken by Msh2-Msh6 and Msh2-Msh3, despite the similarity of their structures.

Dataset Information

DNA mismatch repair gene MSH6 implicated in determining age at natural menopause.

Publications

DNA mismatch repair gene MSH6 implicated in determining age at natural menopause.

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