Genetic instability and Cancer
How can a normal cell become a cancer cell?
Understanding the basis ofcancer is directly linked to the molecular understanding of life and death, acentral question in biology. Cancer nowadays is considered as a disease ofgenetic instability. That is, accumulated mutations in our genes promoteunlimited cell growth, escape from death, invasion, and metastasis.
To obtainthese seemingly impossible properties, thousands of genes must be mutated.However, the calculated normal mutation rate (10-7/gene/generation)never allows a normal cell to become a cancer cell in our lifetime.
Thus,initiation of tumorigenesis must accompany mutations in a gene (or genes) thatserves a critical role in maintaining genetic integrity. Genes that regulatecell cycle, apoptosis, DNA repair, and chromosome segregation are bestcandidate genes crucial in the maintenance of genetic fidelity. When these aredisrupted, cells then achieve much higher rate mutations (increasing to 105~7 –fold), leading to cancer. That the tumor suppressor genes identified todate from human genetics are mostly involved in cell cycle regulation,apoptosis, and DNA repair supports this view.
One of the most aggressive genetic instability is observed inBRCA2-associated cancers. Individuals who inherit one mutant allele of BRCA2are predisposed to early-onset breast cancer. Heterozygous individuals are bornnormally, but develop cancer when the wild-type allele is lost (Loss-ofheterozygosity, LOH). Therefore, BRCA2 is a tumor suppressor. Studies in BRCA2function has been revealed largely by knockout mouse studies. We now know thatBRCA2 is involved in double stranded DNA (DSB) break repair by binding andregulating Rad51. Hence, BRCA2 is essential in error-free repair.
However, the cause of early-onset aneuploidy and abnormal cell cycleregulation are also associated with BRCA2-mutated cancers, in addition toaberrant chromosome translocations due to impaired DSB repair. We areinterested in understanding the role of BRCA2 in the regulation of properchromosome segregation. We believe this is the key to understanding the causeof aneuploidy and massive genetic alteration, a hallmark of BRCA2-associatedcancer.
We also try to understand the link between aging and cancer. In this vein,we have observed that BRCA2 may be involved in telomere maintenance. Thisfunction is likely to be associated with BRCA2’s role in DNA repair ininterphase, S phase, opposed to BRCA2’s role in mitotic cell cycle.
Our efforts to understand the pathogenesis of cancer are not restricted toa single experimental system. We have established mouse models and zebrafishmodels, as well as the cell culture system for biochemistry and molecular cellular biology. By combining in vitroand in vivo systems, we anticipate tounderstand as a whole how normal cells turn into cancer.
Specific Research Projects
Roles of the tumor suppressor BRCA2 in DNA repair and cell cycle control.
Regulation of mitosis and the development of chromosome instability incancer (CIN)
Telomere maintenance and cancer susceptibility
Development and analyses of mouse and zebrafish models for CIN type cancer.
Experimental Systems
Conditional knockout mouse, Knock-in mouse, Transgenic mouse
Zebrafish genetics
Mammalian Cell culture
Patients’ sample