Our Research Work:
Chromatin is a unique bearer of the cell’s genetic and epigenetic identity. Any compromise to its integrity, could have catastrophic consequences. To maintain their integrity, cells have developed an evolutionarily conserved array of interlocked pathways to mend DNA damage; collectively known as the DNA damage response (DDR).
Adequate DDR signaling in the context of chromatinized DNA requires both genetic and epigenetic modifications. Failure to do so compromises genomic stability and could lead to developmental defects and cancer.
Adequate DDR signalling in the context of chromatinized DNA requires both genetic and epigenetic modifications. Failure to do so compromises genomic stability and could lead to developmental defects and cancer.
Fig 2: The rearranged immunoglobulin (Ig) locus where AID-induced mutagenesis and MMR-mediated error-prone DNA repair at Variable and Switch regions promote SHM & CSR, resp. Green arrowhead signify AID mutations. Off-target effect of this process on non-Ig genes (right) could lead to genomic instability and cancer.
Fig 1: DNA damage repair pathways dictate class-switch recombination (CSR) efficiency. An overview of the histone modifications, and the writers and readers associated with them that are essential for CSR, as well as suggestions of additional likely factors. Color = confirmed in NHEJ and CSR, Gray = DNA damage repair factors not yet shown to affect CSR. The key proteins and histone modifications that have been shown to be essential for resolving the DNA double-strand breaks in CSR are summarized. A common theme is the recruitment of 53BP1, which is essential for efficient repair and isotype switching. Importantly, these repair pathways also function in NHEJ. Additional DNA damage repair proteins and histone modifications that have not yet been shown to play a role in CSR are indicated in gray. Some proteins and histone marks involved in other repair pathways, such as homologous recombination (HR), are also indicated in the figure. As these pathways inhibit the NHEJ pathways, they may provide negative control of CSR. Indeed, knockdown of BRCA1 has been shown to increase isotype switching
Exceptions to this general rule, whereby certain cell types deliberately orchestrate the generation of DNA damage to mediate germline or somatic diversity, offer a highly tractable experimental and clinical approach to understand the mechanisms governing DDR. An example of this process is the initiation of somatic hypermutation and double strand break formation during B cell class switch recombination through the selective mutator AID, a member of the APOBEC family of cytosine deaminases.
Fig 3: Epigenomic modifications directing antibody-diversification processes somatic hypermutation (SHM) and CSR. Green core histones and associated modifications are involved in chromatin de-compaction and enable transcription through the immunoglobulin (Ig) locus. All factors above the locus are important for the generation of DSBs while everything below encourages mutagenic repair at the V region, and DSB repair at donor and acceptor S regions (Sμ and Sx, respectively). Blue histones and affiliated modifications help recruit or tether AID and other factors that facilitate production of DSBs. Purple DNA and RNA are linked with sequences and structures that facilitate AID recruitment or targeting. Red core histones and accessory modifications recruit DNA repair proteins to ensure excision of intervening CH region for successful class switching as well as error-prone polymerases to the V region.
Misregulation of these complex processes can lead to detrimental effects, such as:
autoimmunity, immunodeficiencies, tumorigenesis, and accelerated aging through both genetic and epigenetic modifications.