Cancers can exhibit gross chromosomal rearrangements (GCRs) that are complex involving multiple chromosomes, yet their genesis is unknown. We discovered two pathways that rearranged chromosomes by fusing (recombining) inverted repeats found in the DNA sequence. DNA is composed of four building blocks and based on their order (or sequence) can code for important macromolecules like proteins. Repeats are short stretches of DNA sequence that are present in the same or nearly the same order. The human genome (the combination of all chromosomes) is filled with repeats. Thus, we found two separable mechanisms that recombine these repeats to change chromosome structure and potentially cause cancer. The first pathway recombined identical repeats and is consistent with HR. The HR pathway normally repairs breaks in chromosomes to maintain genome integrity. We have also found that defects in HR cause GCRs. Therefore, HR is important for maintaining genome integrity but can also rearrange chromosomes when inappropriately acting on repeat sequences. The second pathway recombined mismatched repeats and is consistent with error-free post replication repair (EF-PRR). EF-PRR normally induces bypass of genetic abnormalities at the point of replication (the process of duplicating DNA that must occur for cells to divide). Lesion bypass can facilitate DNA replication and prevent breaks that can cause rearrangements. Therefore, similar to HR, EF-PRR's inappropriate action on repeats can rearrange chromosomes. Both repeat fusion mechanisms caused very complicated GCRs that involved multiple chromosomes similar to those found in some cancers. Thus, HR and EF-PRR are two pathways the can structurally rearrange chromosomes similar to the GCRs found in some cancers. Our immediate goal is to further elucidate the role both HR and EF-PRR play in cancer development and our long-term goal is to design protocols that manipulate these pathways for both cancer prevention and therapy.
Click Here to view Dr. Hasty's Department of Molecular Medicine webpage