Research Institute in Oncology and Hematology

Sachin Katyal

DNA Damage and Repair

Associations:
Assistant Professor, Department of Pharmacology and Therapeutics, University of Manitoba;
Senior Scientist, Research Institute in Oncology and Hematology, CancerCare Manitoba

Degrees:
B.Sc. in Biochemistry, Univ. of Alberta, Canada, 1999
Ph. D. in Oncology, Univ of Alberta, Canada, 2005
Asst. Professor, University of Manitoba, Dept of Pharmacology and Therapeutics

Contact:
675 McDermot Ave
Winnipeg, Mb R3E 0V9
ph.: 204-787-2765, fax: 204-787-2190
Email: Dr Sachin Katyal PhD

Sachin Katyal, Ph.D.

Modulating DNA Damage repair mechanisms to enhance brain tumour treatment success

DNA strand breaks occur on a daily basis in cells due to cell stress, environmental factors, oxidation and metabolism. Damaged DNA is resolved by dedicated DNA damage response (DDR) and repair mechanisms in order to preserve genomic integrity and cell function. The goal of conventional chemotherapeutic drugs and radiotherapy is to elicit DNA damage to overwhelm the tumour’s innate DDR and induce cell death. However, tumour cells have remarkable ability to respond to DNA damage, repair and adapt thus allowing survival and eventual drug resistance. It is predicted that >90% of all tumours incur at least one defect in the DNA damage response (DDR), thus tumour cell survival relies upon enhanced activity of other compensatory DNA repair pathways. The aggressive and deadly brain tumour, glioblastoma multiforme (GBM) shows a very high level of recurrence due to emergence of chemo/radio-resistant tumour cell populations; patients usually live about 1 yr from their date of diagnosis. We are identifying the “back-up” DNA repair pathways in these deadly brain tumours so that we can enhance the patients’ treatment success and their quality-of-life.

DNA repair pathways are guardians of the cellular genome.

Every individual human cell is estimated to incur tens of thousands of DNA strand breaks due to environmental stress, oxidation, metabolic function and DNA decay. To preserve genomic integrity, these breaks are resolved by dedicated DNA damage repair (DDR) pathways that ensure faithful transmission of genomes in dividing cells to ensure proper cell function and survival. There are two classes of DNA strand breaks, double-strand breaks (DSBs) and DNA single-strand breaks (SSBs), which are resolved by specific repair pathways, DSBR and SSBR. The inability to properly process and repair SSBs can interfere with the DNA replication and transcriptional machinery resulting in persistent SSBs, formation of the particularly genotoxic DNA double-stranded break (DSB) lesion and aberrant gene expression resulting in a variety of cellular pathology, including: senescence, cancer and apoptosis. It is known that the diverse mechanisms involving cell cycle regulation, DDR pathways, cellular metabolism, and cell death act in concert in response to DNA damage. As such, cellular life and death decisions are balanced by these mechanisms as defective DDR in proliferating cells, including neuroprogenitors, can lead to cancer, while defective neuronal DDR can lead to neurodegeneration.

Anti-tumorigenic agents overwhelm cellular DNA repair responses with lethal levels of genotoxicity.

The objective of common front-line radiation and chemotherapeutic strategies used in the treatment of brain tumours is to induce DNA breaks so as to overwhelm the cellular DNA repair machinery thus promoting genomic damage and tumour cell death. However, as the intrinsic cellular DNA repair process counteracts the therapeutic efficacy of this strategy, high radiation and drug doses are required which result in harmful neural and systemic side effects. My research seeks to identify ways to dysregulate cellular DNA repair pathways in tumours and improve therapeutic success. In this regard, DNA damage repair pathways are an ideal clinical target as we can specifically kill cancer cells by lowering the radio- and chemotherapeutic threshold of tumour cell genotoxicity by inhibiting redundant DNA repair pathways.

My research uses advanced molecular, biochemical and genetic techniques to gain insight into the biology of mammalian DNA strand break repair pathways. My goal is to identify ways to manipulate these pathways to develop novel treatment strategies in the clinical management of cancer. We are seeking a very highly motivated postdoctoral fellows (with a strong history of previous success) to join our team.


Team Members

  • Bozena Kuzio (Lab Manager)
  • Ali Saleh (Research Associate)

  • Daniel Huang (Summer Student 2015 - present)
  • Presentations:
    • Understanding Top-1 biology in Glioblastoma Multiforme. CCMB Summer Student Research Day (2015). CancerCare Manitoba, Winnipeg, MB, Canada.
    Awards and Honours:
    • Brain Tumour Foundation of Canada Studentship (2015-2016). Understanding Top1 biology in the treatment of malignant brain tumours.
    • 1st Place, Best Research Presentation, CCMB Summer Student Research Day (2015). Understanding Top-1 biology in Glioblastoma Multiforme. CancerCare Manitoba, Winnipeg, MB, Canada.
  • Matthew Packer (BSc Med 2014 - present)
  • Presentations:
    • Co-inhibition of Redundant DNA Repair Pathways in the treatment of malignant glioma. CCMB Summer Student Research Day (2014). CancerCare Manitoba, Winnipeg, MB, Canada.
    • Chemoradiosensitization of Malignant Glioma through Co-inhibition of Redundant DNA Repair Pathways. BScMed Student Thesis Presentation (2015). University of Manitoba, Winnipeg, MB, Canada.
    • Joe Doupe Memorial Lecture (2015). Chemoradiosensitization of Malignant Glioma through Co-inhibition of Redundant DNA Repair Pathways. University of Manitoba, Winnipeg, MB, Canada.
    Awards and Honours:
    • Joe Doupe Memorial Lecture (2015).
    • Outstanding oral presentation
    • Mr. Justice James E. Wilson Memorial Award for Excellence and Outstanding Promise in Research during the 1st summer of the BScMed Program
    • Dr. Lyonel Israels Memorial Award for excellence and outstanding promise in research based on the quality of the final written report as well as the oral presentation at the completion of the BScMed program
    • BScMed Program Travel Award to attend the National Research Forum in Galveston, Texas in 2016
  • Asha Sinha (Graduate Student 2015 - present)
  • Presentations:
    • Harnessing microglia as a novel glioblastoma therapy (2015). Manitoba Neuroscience Network Annual Retreat. Winnipeg, MB, Canada.
    • Harnessing microglia as a novel glioblastoma therapy (2015). CancerCare Manitoba Research Day. Winnipeg, MB, Canada.
    • Harnessing microglia as a novel glioblastoma therapy (2015). CancerCare Manitoba, Research Institute in Oncology and Hematology Annual Retreat, Steinbach, MB, Canada.
    • Harnessing microglia as a novel glioblastoma therapy (2015). Canadian Cancer Research Conference, Montreal, QC, Canada.
    Awards and Honours:
    • Best Poster Presentation, Manitoba Neuroscience Network Annual Retreat (2015). Harnessing microglia as a novel glioblastoma therapy. Winnipeg, MB, Canada.
    • International Graduate Student Award, U. Manitoba (2015).
    • 1st place, Three-minute thesis (3MT) competition, CancerCare Manitoba, Research Institute in Oncology and Hematology Annual Retreat
  • Rajas Tipnis (Undergraduate research student 2013 - present )
  • Presentations:
    • Inhibition of the DNA single-strand break repair pathway in the treatment of malignant brain tumours. CCMB Summer Student Research Day (2014). CancerCare Manitoba, Winnipeg, MB, Canada.
    • Inhibition of the DNA single-strand break repair pathway in the treatment of malignant brain tumours. Undergraduate Research Poster Competition (2014). University of Manitoba, Winnipeg, MB.
    • Xrcc1 and TDP1 co-inhibition combined with camptothecin to treat malignant pediatric medulloblastoma. CCMB Summer Student Research Day (2015). CancerCare Manitoba, Winnipeg, MB, Canada.
    • Co-inhibition of Xrcc1 and TDP1 chemosensitizes pediatric medulloblastoma Undergraduate Research Poster Competition (2015). University of Manitoba, Winnipeg, MB.
    Awards and Honours:
    • Brain Tumour Foundation of Canada Studentship (2013-2014).
    • ICCHA Award (2013).
    • City of Winnipeg Youth Role Model Award (2014).
    • University of Manitoba Undergraduate Research Award (2015).
    • 2nd place – “Health Sciences” University of Manitoba Undergraduate Research Poster Competition (2015).
  • Marina Mostafizar (Graduate Student 2015 - present)
  • Awards and Honours:
    • Nickerson Award, U. Manitoba (2015).

Publications since 2011

  1. Heo J, Li J, Summerlin M, Hays A, Katyal S, McKinnon PJ, Nitiss KC, Nitiss JL, Hanakahi LA TDP1 promotes assembly of non-homologous end joining protein complexes on DNA. DNA Repair (Amst). 2015 Jun;30:28-37. doi: 10.1016/j.dnarep.2015.03.003. Epub 2015 Mar 17.
  2. Katyal S, Lee Y, Nitiss KC, Downing SM, Li Y, Shimada M, Zhao J, Russell HR, Petrini JH, Nitiss JL, McKinnon PJ. Aberrant topoisomerase-1 DNA lesions are pathogenic in neurodegenerative genome instability syndromes.Nat Neurosci. 2014 Jun;17(6):813-21. doi: 10.1038/nn.3715. Epub 2014 May 4.
  3. Shokolenko, I.N., Fayzulin, R., KATYAL, S., McKinnon, P.J., Wilson, G.L., Alexeyev, M.F. (2013). Mitochondrial DNA ligase activity is dispensable for viability, but is essential for mtDNA maintenance. J. Biol. Chem. Epub 23884459. ISI IF:4.7
  4. Lee, Y., Katyal, S., Downing, S., Zhao, J., Russell, H.R., McKinnon, P.J. (2012). Neurogenesis requires TopBP1 to prevent catastrophic replication-associated DNA damage in early progenitors. Nat. Neurosci. 15: 829-826. ISI IF:15.3
  5. Lee, Y., Shull, E.R.P., Frappart, P.-O., Katyal, S., Enriquez-Rios, V., Zhao, J., Russell, H.R., Brown, E.J., McKinnon, P.J. (2011). ATR maintains select progenitors during nervous system development. EMBO J., 31: 1177-1189. ISI IF:9.8 TC:4
  6. Katyal, S., Glubrecht, D.D., Guo, Z., Li., L. and Godbout, R. (2011). Disabled-1 alternative splicing in human fetal retina and neural tumours. PLoS One, 6: e28579. ISI IF:3.7 TC:3
  7. Katyal, S. and McKinnon, P.J. (2011). Disconnecting XRCC1 and DNA ligase III. Cell Cycle. 10: 2269-2275. ISI IF:5.2 TC:1
  8. Simsek, D., Brunet, E., Wong, Y.-W., Katyal, S., Gao, Y., McKinnon, P.J., Lou, J., Zhang, L., Li, J., Rebar, E., Gregory, P., Holmes, M. and Jasin, M. (2011). DNA ligase III promotes alternative nonhomologous end-joining during chromosomal translocation formation. PLoS Genet. 7: e1002080. ISI IF:8.5 TC:28
  9. *Gao, Y., *Katyal, S., Lee, Y., Zhao, J., Rehg, J.E., Russell, H.R. and McKinnon, P.J. (2011). Ligase III is critical for mtDNA integrity but not Xrcc1-mediated nuclear DNA repair. Nature. 471: 240-244. *Equal Contribution ISI IF:38.6 TC:31

PUBLISHED BOOK CHAPTERS

  1. KATYAL, S. and McKinnon, P.J. (2009). 'Mouse Models of DNA Double Strand Break Repair Deficiency and Cancer', in K.K. Khanna and Y. Shiloh (eds.), The DNA Damage Response: Implications on Cancer Formation and Treatment, Springer Press, New York, 285-305.

Research Funding as Principal Investigator

2016 - 2018 CancerCare Manitoba Foundation Operating Grant
"Understanding Topoisomerase biology in the treatment of malignant brain tumours"

2015-2020 CIHR New Investigator Salary Award
“Modulation of the DNA damage repair (DDR) response in the treatment of brain tumours.”

2015 - 2020 Research Manitoba Cluster Grant
(co-Investigator), “An Innovative Cancer Research Model: Integrated Multidisciplinary CLL Research Cluster”.

2014 - 2019 Canadian Institutes of Health Research (CIHR) Open Operating grant
"ATM and TDP1 coordinate neurodevelopment and modulate Top1-mediated anti-cancer therapeutic outcome"

2014 - 2016 Research Manitoba (formerly MHRC) Operating Grant
"Modulating the cellular DNA single strand break repair pathway to improve treatment of pediatric brain tumours"

2014- 2015 Canadian Institutes of Health Research Open Operating Grant
"ATM and TDP1 coordinate neurodevelopment and modulate Top1-mediated anti-cancer therapeutic outcome"

2014 CancerCare Manitoba Foundation (CCMF) Operating Grant
"Modulating the cellular DNA single strand break repair pathway to improve treatment of pediatric brain tumours"

2014 CancerCare Manitoba Foundation (CCMF) and Research Manitoba (formerly MHRC) Partnered Program grant (MPP)
"ATM and TDP1 coordinate neurodevelopment and modulate Top1-mediated anti-cancer therapeutic outcome"

2013 University of Manitoba, University Research Grants Program (URGP)
"Inhibition of the DNA single-strand break repair pathway in the treatment of malignant brain tumours"

2013 CancerCare Manitoba Foundation Equipment Grant
RadSource RS2000 Irradiator

2013 - 2016 Research Manitoba (formerly MHRC) Establishment Award - $100,000
"Modulation of the DNA damage repair (DDR) response as a novel anti-cancer treatment strategy"

2013 Canadian Cancer Society Research Institute Junior Investigator Award

Academic and Administrative Service:

  1. Member of grant review panel - Netherlands Organization for Scientific Research (2014-present)
  2. Member of program review panel - Canada Research Chair Tier 2 program (2014-present)
  3. Member of grant review panel - Manitoba Health Research Council Postdoctoral Awards (2014-present)
  4. Member of grant review panel - Cancer Research Society Operating Grants competition (2014-present), "Oncogenes and Tumour Supressors" panel.
  5. Invited speaker - CancerCare Manitoba Foundation Scotiabank Fundraiser (2014-present)
  6. Member of thesis review panel - Simon and Sarah Israels Graduate Thesis Award (2013-present).
  7. Co-founded the University of Manitoba Brain Tumour Research group (BTRG), comprising of four principal investigators and their laboratories with research interest in medulloblastoma and glioma research.
  8. Reviewer for Molecular Cancer Research
  9. Reviewer for Journal of Radiation Research
  10. Coordinator of University of Manitoba Faculty of Medicine Graduate and Postdoctoral Trainee Professional Development Workshop (2014-present).
  11. Judge - CancerCare Manitoba Annual Research Day for Trainees (2013-present).
  12. Judge - CIHR National Health Research Poster Competition (2013-present).

Awards and Professional Service

Postdoctoral Training

2010 - ATW 2010 Young Investigator Award
2008 - Canadian Institutes of Health Research Postdoctoral Fellowship (declined)
2008 - Neoma Boadway AP Endowed Postdoctoral Fellowship
2008 - ATW 2008 Young Investigator Award
2007 - Keystone Symposia Scholarship Genome Instability and Repair

Graduate Studies

2004 - Elizabeth Tucker PhD Student Award, Dept. of Oncology, University of Alberta
2004 - ASCB 44th Annual Meeting Student Travel Award, American Society for Cell Biology
2004 - Dr. Cyril Kay Graduate Studentship, Alberta Cancer Board
2003 - ACB Graduate Studentship, Alberta Cancer Board
2002 - Endowed Graduate Studentship in Oncology, Dept. of Oncology, University of Alberta
2002 - Mary Louise Imrie Graduate Award, Faculty of Graduate Studies, University of Alberta
2002 - Meltzer Award, Dept. of Oncology, University of Alberta
2002 - Medical Sciences GAP Award, Faculty of Medicine and Dentistry, University of Alberta



RIOH gratefully acknowledges the generous support of



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