Homologous recombination-mediated DSB repair
Homologous recombination (HR) is a major error-free pathway for the repair of damaged chromosomes and maintenance of genomic integrity. As such, dysregulation of the HR pathway is associated with various human diseases such as cancers. How HR is tightly regulated and what are the underlying molecular mechanisms are fundamental questions. I have along-standing interest in deciphering the mechanistic action of HR through use of biochemical, biophysical and cell-based approaches. My laboratory has successfully established an in vitro-reconstituted HR methodology and conducted cell-based analyses to delineate the mechanism of the homologous recombination machinery. Our research has demonstrated how the DNA repair activity of RAD51 recombinase is regulated by cellular chemicals, such as polyamines (see figure). We continue to study how RAD51 repair activity is regulated by its interacting proteins to fulfill its biological needs.
Apart from our contributions to fundamental research, my laboratory is also committed to translating the knowledge acquired from basic research into approaches for diagnosing and treating cancers induced by deficiencies in recombination-mediated DNA repair. In recent years, clinical studies have found that cancer cells, such as breast cancer and ovarian cancer,respond well to specific drug treatments (such as PARP inhibitors) if those cells carry mutations in HR genes (such as BRCA1 or BRCA2). Consequently, a functional assay to measure HR efficiency in patient samples is sorely needed.We have successfully developed an adenovirus-based HR reporter system to directly measure the HR activity of cancer cells. A clinical study using this functional analysis is ongoing. This detection technology can be more directly and accurately reflect the HR efficiency of cancer cells than existing methodologies.
Selected publications:
The mechanistic role of recombination machinery in replication fork restart
During replication stress, stalled/collapsed replication forks need to be reinitiated to complete DNA replication. It has been well established that recombination machinery such as BRCA2 and RAD51 plays a crucial role in regulating the stability of remodeling forks. Our recent study demonstrated that CST and RPA proteins could co-occupy the same ssDNA molecule, and CST interacted with RAD51 directly at the protein-to-protein level, bringing RAD51 to RPA-bound ssDNA (see figure). As such, CST promotes subsequent DNA replication repair. Currently, we are studying how the components of recombination machinery participate in replication fork restart and their molecular mechanisms.
Selected publications:
The mechanism of meiotic recombination in meiosis
Apart from representing a major error-free DNA repair pathway to repair chromosomal lesions by precisely exchanging almost identical DNA sequences between sister chromatids, homologous recombination (HR) also exerts a specialized function in recombining similar but non-identical DNA sequences between parental chromosomes during meiosis. As such, the fidelity of recombining DNA sequences needs to be tightly regulated during meiotic recombination. Our very recent study conducting a structure-function relationship analysis elucidates how evolutionarily conserved amino acid residues in DMC1 intrinsically influence the mismatch tolerability of the recombinase (see inline figure). How “fidelity control” of recombinases can be achieved intrinsically and extrinsically is under investigated.
Selected publications:
Homologous recombination-mediated DSB repair
Homologous recombination (HR) is a major error-free pathway for the repair of damaged chromosomes and maintenance of genomic integrity. As such, dysregulation of the HR pathway is associated with various human diseases such as cancers. How HR is tightly regulated and what are the underlying molecular mechanisms are fundamental questions. I have along-standing interest in deciphering the mechanistic action of HR through use of biochemical, biophysical and cell-based approaches. My laboratory has successfully established an in vitro-reconstituted HR methodology and conducted cell-based analyses to delineate the mechanism of the homologous recombination machinery. Our research has demonstrated how the DNA repair activity of RAD51 recombinase is regulated by cellular chemicals, such as polyamines (see figure). We continue to study how RAD51 repair activity is regulated by its interacting proteins to fulfill its biological needs.
Apart from our contributions to fundamental research, my laboratory is also committed to translating the knowledge acquired from basic research into approaches for diagnosing and treating cancers induced by deficiencies in recombination-mediated DNA repair. In recent years, clinical studies have found that cancer cells, such as breast cancer and ovarian cancer,respond well to specific drug treatments (such as PARP inhibitors) if those cells carry mutations in HR genes (such as BRCA1 or BRCA2). Consequently, a functional assay to measure HR efficiency in patient samples is sorely needed.We have successfully developed an adenovirus-based HR reporter system to directly measure the HR activity of cancer cells. A clinical study using this functional analysis is ongoing. This detection technology can be more directly and accurately reflect the HR efficiency of cancer cells than existing methodologies.
Selected publications:
The mechanistic role of recombination machinery in replication fork restart
During replication stress, stalled/collapsed replication forks need to be reinitiated to complete DNA replication. It has been well established that recombination machinery such as BRCA2 and RAD51 plays a crucial role in regulating the stability of remodeling forks. Our recent study demonstrated that CST and RPA proteins could co-occupy the same ssDNA molecule, and CST interacted with RAD51 directly at the protein-to-protein level, bringing RAD51 to RPA-bound ssDNA (see figure). As such, CST promotes subsequent DNA replication repair. Currently, we are studying how the components of recombination machinery participate in replication fork restart and their molecular mechanisms.
Selected publications:
The mechanism of meiotic recombination in meiosis
Apart from representing a major error-free DNA repair pathway to repair chromosomal lesions by precisely exchanging almost identical DNA sequences between sister chromatids, homologous recombination (HR) also exerts a specialized function in recombining similar but non-identical DNA sequences between parental chromosomes during meiosis. As such, the fidelity of recombining DNA sequences needs to be tightly regulated during meiotic recombination. Our very recent study conducting a structure-function relationship analysis elucidates how evolutionarily conserved amino acid residues in DMC1 intrinsically influence the mismatchtolerability of the recombinase (see inline figure). How “fidelity control” of recombinases can be achieved intrinsically and extrinsically is under investigation.
Selected publications:
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