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Brief Profile of the Awardee

awardee

Dr Ganesh Nagaraju

  • 2018
  • Biological Sciences
  • 30/04/1973
  • DNA Repair, Chromosome Instability, Genetic Diseases and Cancer
Award Citation:

Academic Qualifications:
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Thesis and Guide details:
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Details of CSIR Fellowship/ Associateship held, if any or from other sources/ agencies.
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Significant foreign assignments:
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(a) Significant contributions to science and/ or technology development by the nominee based on the work done in India during most part of last 5 years:
The main focus of the nominee is to understand genomic alterations affecting homologous recombination (HR), DNA replication and repair, gene amplification and the associated mutations that form the basis for tumorigenesis with the long-term goal of developing molecules to target the pathology. Germline mutations in the genes that regulate HR and genome integrity cause various genetic disorders including Fanconi anemia (FA). Mammalian RAD51, an ortholog of bacterial RecA protein plays a key role in homologous recombination (HR) and genome maintenance. Mammalian genome encodes five RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3). Germline mutations in the genes that regulate HR and genome integrity cause various genetic disorders including FA. Using genetic, cytogenetic and cell biological as well as biochemical approach, the nominee demonstrated that RAD51C (FANCO) is indeed a novel gene in the FA pathway of DNA interstrand cross-link (ICL) repair. His group showed that RAD51C plays a downstream role in the FA pathway ICL repair. More interestingly, they find that RAD51C regulates intra-S-phase checkpoint and repair distinctly. These findings have implications for FA and breast and ovarian cancer susceptibility (JBC, 2012). For the first time nominee identified that XRCC3 S225 is a novel phosphorylation target of ATM and ATR kinases. He demonstrated that XRCC3 S225 phosphorylation is crucial for DNA double-strand break (DSB) repair by HR and intra-S-phase checkpoint regulation as well as maintenance of genome integrity (MCB, 2013). These contributions were recognized with the award of B.M. Birla Science Prize in Biology to the nominee for the year 2012. Replication forks are susceptible for breakage if unprotected when the forks stall due to template damage, various secondary structures and DNA bound proteins. BRCA2 tumor suppressor and FA pathway proteins are known to protect the stalled forks. Nominee’s recent and elegant study finds that RAD51 paralogs in distinct complexes protect and restart the stalled forks. They demonstrated that RAD51 paralogs protect the stalled forks in a non-epistatic manner to BRCA2. The restart of the stalled forks is dependent on ATP hydrolysis by CX3 complex. Notably, the pathological mutants of RAD51C were defective for fork protection, implying the tumor suppressor and essential functions of RAD51 paralogs in genome maintenance (NAR, 2015). These contributions were recognized with National Bioscience award from DBT and Sir CV Raman young scientist award from Government of Karnataka for the year 2015. Gene amplification is commonly found in various types of cancer and the mechanism underlying such amplifications/duplications is largely unclear. Moreover, the role of FANCJ helicase in the FA pathway of ICL/DSB repair is less understood. Nominee’s most recent study demonstrated that FANCJ helicase suppresses gene duplication/amplifications during repair of DSBs by sister chromatid recombination, providing insights into the mechanism of pathological repair leading to tumorigenesis (NAR, 2017). Mutations in mitochondrial genome and its instability are linked to various genetic diseases, premature aging and cancer. The factors and the mechanism by which integrity of the mitochondrial genome is maintained are poorly understood.
(b) Impact of the contributions in the field concerned:
Fanconi anemia (FA) is a genetic disorder caused by germline mutations in the genes that are known to play a role in DNA repair. This disease is primarily found in children and is characterized by developmental abnormalities, bone marrow failure and cancer. Understanding the molecular basis of disease would provide insights into the novel strategies for the treatment and prevention of this disease. So far there are 21 genes identified to play a role in FA pathway of DNA interstrand cross-link (ICL) repair. RAD51 paralog RAD51C was identified as a 14th gene in this pathway. Nominee has established that RAD51C is a FA as well as breast and ovarian cancer susceptibility gene. This elegant work contributed significantly to the understanding of FA-like disorder with germline mutations in RAD51C. Moreover, this work also provided insights into the development of cancer with germline mutations in RAD51C.  Germline mutations in RAD51 paralogs are known to cause various types of cancer including breast and ovarian cancers. However, the underlying mechanism(s) by which mutations in RAD51 paralogs contribute to cancer is unclear. The nominee identified that 8 XRCC3 serine 225 undergoes phosphorylation in a DSB specific manner by ATM and ATR kinases. He demonstrated that XRCC3 phosphorylation is essential for the execution of intra-S-phase checkpoint and DSB repair by HR. This elegant study provided insights into the mechanism of genome maintenance and tumor suppression via XRCC3 phosphorylation.  Error free duplication of the genome is crucial for the maintenance of genome integrity in all organisms. Replication associated DNA lesions are the primary cause of chromosome instability which is frequently found in various types of cancer cells. RAD51 paralogs are essential for cell viability. However, despite their identification over nearly two decades ago their essential functions remain enigmatic. The nominee’s most recent and elegant study demonstrated that RAD51 paralogs in distinct complexes protect and restart the stalled forks. This work provides insights into the development of FA-like disorder and tumorigenesis. In my opinion this work is highly significant and has a great impact in the field of RAD51 paralogs.  Gene amplification is one of the hallmarks of cancer cells. Oncogene duplications/amplifications can promote tumorigenesis. However, the mechanisms underlying such amplifications/duplications are unclear. Nominee’s recent study identifies the novel function of FANCJ helicase whose mutations are known to cause FA disorder in suppressing gene amplifications/duplications. His study provides insights into the tumor suppressor function of FANCJ helicase.  Mutations in mitochondrial genome and its instability are known to cause various genetic diseases, premature aging and cancer. The molecular mechanism and the factors that are involved in maintaining integrity of the mitochondrial genome is less understood. Nominee identifies a novel function of RAD51 paralogs in facilitating mitochondrial DNA replication and in the repair of spontaneously arising lesions to maintain stability of the mitochondrial genome.  In a collaborative research, nominee has developed a novel photo-inducible ICL molecule which can be activated by visible light.
Places where work of last 5 years has been referred/ cited in Books, Reviews:
(i). Paper Cited
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(ii). Book Cited
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Names of the industries in which the technology (ies) has (have) been used :
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The achievements already been recognised by Awards by any learned body:
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The Awardee a fellow of the Indian National Science Academy/Indian Academy of Sciences/National Academy of Sciences/Others:
The Awardee delivered invited lecture(s) in India/abroad and/or chaired any scientific Internatiional Conference Symposium:
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List of Awardee's 10 most significant publications.
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List of Awardee's 5 most significant publications during the last 5 years
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List of Awardee's 5 most significant publications from out of work done in India during the last five years:
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Complete list of publications in standard refereed journals:
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Complete list of publications with foreign collaborators (indicating your status as author):
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List of papers published in Conferences /Symposia/ Seminars, etc:
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List of the most outstanding Technical Reports/ Review Articles:
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Statement regarding collaboration with scientists abroad:
List of Patents taken
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Total number of patents granted in last five years.
Details of Books published:
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Contact Details


  • Department of Biochemistry
    Indian Institute of Science
    CV Raman Road
    Bangalore - 560012
    Karnataka INDIA
  • nganesh[at]iisc[dot]ac[dot]in
11 Dec 2018, http://ssbprize.gov.in/Content/Detail.aspx?AID=536