The Effect And Mechanism Of Cigeratte Smoke Condensate, Arsenic And Acrolein To DNA Mismatch Repair

The importance of DNA mismatch repair (MMR) in maintaining genomic stability is underscored by the fact that loss of MMR function results in genome-wide mutations and susceptibility to certain types of cancer syndromes, including hereditary non-polyposis colorectal cancer (HNPCC). It is generally accepted that the MMR system ensures genomic stability by correcting mismatches arising during DNA replication, blocking homologous recombination, and mediating DNA damage induced apoptosis.Generally, there are three steps in MMR:intiation, excision and resynthesis. And several key components such as MutSa. MutLa, ExoI, RPA, PCNA and polymerases which play important roles in several steps of MMR. For example, PCNA works mainly in intiation and resynthesis step. In the intiation step, PCNA recruits MutSa and MutLa and renders them to the right site; In the resynthesis step, PCNA recruits the right polymerase to resynthesis. MutLa works as an endonuclease for 3’substrates in the intiation step and works a signal for excision ending in the excision step.Cigeratte smoke condensate, arsenic and acrolein are mutagenic agents and they are universal in the environment which jeopardize people’s health. Meantime, DNA mismatch repair system is a very important mechanism for protecting DNA damage and genomic instability in human body. However, it is not known whether Cigeratte smoke condensate, arsenic and acrolein alters MMR function, leading to tumor development and progression.In this thesis, cigeratte smoke condensate, arsenic and acrolein were used to treat HeLa cells or HeLa nuclear extract to test whether they altered DNA mismatch repair function.We found that arsenic inhibited DNA mismatch repair by increasing PCNA phosphorylation, diminished PCNA function in initiation step and delayed PCNA function in resynthesis step. Cigeratte smoke condensate inhibited DNA mismatch repair by inhibiting PCNA function in both initiation and resynthesis step. And arsenic and cigeratte smoke condensate had synergistic effect on MMR. Acrolein would crosslink with MutLα and modify MutLa to inhibit MMR directly.It is still unknown the mechanism how cigeratte smoke condensate, arsenic and acrolein result in cancer, this study found that cigeratte smoke condensate, arsenic and acrolein could inhibit DNA mismatch repair which give us some new idea to fight with cancer and look for new drug target for therapy.