BRIC-NIBMG | BRIC National Institute of Biomedical Genomics

Sriram Sridharan

Email: ss16@nibmg.ac.in
Position: Ramalingaswami Fellow
Highest Educational Qualification: PhD

Profile

Research Interest :

Our group is driven by a deep interest in uncovering the fundamental mechanisms that safeguard genome integrity. We explore how cells preserve the stability of their genomes through the intricate interplay of DNA replication, cell cycle regulation, and DNA repair pathways, particularly under conditions of intrinsic and extrinsic stress.

To achieve this, we adopt a multidisciplinary approach that integrates cutting-edge techniques from cell biology, molecular biology, and genomics, enabling us to decode the complex regulatory networks that maintain genomic stability. Ultimately, our goal is to gain mechanistic insights into how genome maintenance is orchestrated and how its failure contributes to carcinogenesis.

Selected Publications:

1. Roy SS, Bagri S, Sengupta A, Regina Then C, Kumar R, Sridharan S, Chowdhury S, “Artificially inserted G-quadraplex DNA secondary structures induce long-distance chromatin activation.”, eLife 13:RP96216 (2024).

2. Gaggioli V, Lo C. S. Y, Reverón-Gómez N, Jasencakova Z, Domenech H, Nguyen H, Sidoli H, Tvardovskiy A, Uruci S, Slotman J. A, Chai Y, Gonçalves S. G. S. C, Manolika E. M, Jensen O. N, Wheeler D, Sridharan S, Chakrabarty S, Demmers J, Kanaar R, Groth A, Taneja N, “Dynamic de novo heterochromatin assembly and disassembly at replication fork ensures fork stability”, Nat Cell Biol 25:1017–1032.

3. Borel V, Boeing S, van Wietmarschen N, Sridharan S, Hill BR, Ombrato L, Perez-Lloret J, Jackson D, Goldstone R, Boulton SJ, Nussenzweig A, Bellelli R, “Disrupted control of origin activation compromises genome integrity upon destabilization of Polε and dysfunction of the TRP53-CDKN1A/P21 axis”, Cell Reports, Volume 39, Issue 9, 31 May 2022, 110871.

4. van Wietmarschen N, Sridharan S#, Nathan WJ, Tubbs A, Chan EM, Callen E, Wu W, Belinky F, Tripathi V, Wong N, Foster K, Noorbakhsh J, Garimella K, Cruz-Migoni A, Sommers JA, Huang Y, Borah AA, Smith JT, Kalfon J, Kesten N, Fugger K, Walker RL, Dolzhenko E, Eberle MA, Hayward BE, Usdin K, Freudenreich CH, Brosh Jr RM, West SC, McHugh PJ, Meltzer PS, Bass AJ & Nussenzweig A, “Repeat expansions confer WRN dependence in microsatellite-unstable cancers”, Nature, Volume 586, pp 292–298(2020).

5. Feng X, Tubbs A, Zhang C, Tang M, Sridharan S, Wang C, Jiang D, Su D, Zhang H, Chen Z, Nie L, Xiong Y, Huang M, Nussenzweig A, Chen J, “ATR inhibition potentiates ionizing radiation-induced interferon response via cytosolic nucleic acid sensing pathways”, EMBO J (2020)39:e104036.

6. Yin M, Baslan T, Walker RL, Zhu YJ, Freeland A, Matsukawa T, Sridharan S, Nussenzweig A, Pruitt SC, Lowe SW, Meltzer PS, Aplan PD, “A unique mutator phenotype reveals complementary oncogenic lesions leading to acute leukemia”, JCI Insight, Volume 4, Issue 23, 17 October 2019.

7. Tubbs A, Sridharan S#, van Wietmarschen N, Maman Y, Callen E, Stanlie A, Wu W, Wu X, Day A, Wong N, Yin M, Canela A, Fu H, Redon C, Pruitt SC, Jaszczyszyn Y, Aladjem MI, Aplan PD, Hyrien O, Nussenzweig A, “Dual Roles of Poly(dA:dT) Tracts in Replication Initiation and Fork Collapse”, Cell, Volume 174, Issue 5, 23 August 2018, pp 1127-1142.

8. Canela A, Sridharan S, Sciascia N, Tubbs A, Meltzer P, Sleckman BP, Nussenzweig A, “DNA Breaks and End Resection Measured Genome-wide by End Sequencing”, Molecular Cell, Volume 63, Issue 5, pp 898–911, September 2016.

# indicates joint first author

Research

Research:

Cells undergoing cellular replication need to duplicate their DNA, a complex process regulated spatially and temporally by a plethora of proteins. Dysregulation of this critical process results in induction of genome instability, a hallmark of cancer. Consequently, any action that interferes with the ability of the cell to faithfully replicate their DNA is known as replication stress and can induce genome instability, an all-encompassing term that reflects myriad forms of DNA damage and the ensuing adverse consequences that come from an inability to repair and process this damage. Therefore, understanding the genomic contexts in which replication stress is induced is crucial to the understanding of cancer etiology.

Sources of replication fork stalling and replication stress. Such situations can give arise to duplicated DNA with errors which gives arise to genome instability.

Replication stress either through endogenous or exogenous sources can cause incomplete and unfaithful replication by stalling and/or terminating the replication machinery prematurely resulting in DNA lesions, the most deleterious being the Double Strand Breaks (DSBs). There are many impediments to progression of replication forks as shown. When cells are subject to replication stress, replication forks are stalled and triggers the activation of downstream process that promotes resolution of the stress and subsequent restart of the replication forks (RFs). These processes are collectively known as the S-phase checkpoint. This leads to DNA replication forks that are stalled to form various structures under a mechanism known as fork protection. The persistent stalling of RFs is characterized by stretches of single stranded DNA (ssDNA) which result from the uncoupling of the DNA helicase, which is used to unwind DNA ahead of the DNA polymerase and the DNA helicase itself. Stalled forks that are unable to restart resolve into DSBs which the cell tries to repair. DSBs can be repaired through two major pathways- homologous recombination (HR) and non- homologous end joining (NHEJ). Cancer therapeutics that target the DNA repair pathway, operate by elevating the level of endogenous replication stress in cancer cells and force them to undergo apoptosis. These drugs induce/elevate replication stress in various ways including nucleotide (dNTP) depletion, DNA polymerase inhibition, and inhibiting helicases necessary for restarting stalled replication forks.

Our overarching goal is to understand why, where and what of the (epi)genome acts as an impediment to faithful DNA replication. To this end, we will take a hybrid approach to perform in-house experimentation in cell and molecular biology as well as in genomics including Next-Generation Sequencing (NGS). Using our in-house and publicly available NGS datasets we will also develop computational/statistical models that tease out the (epi)genomic contexts that make them barriers to DNA replication, response of the cells to this stress and mechanisms by which the cell overcomes this stress.

Research Funding:

Year	Title	Funding Agency	Role
2025-2028	Mechanisms of replication for stabilization	Ramalingaswami Re-entry Fellowship (RRF), Department of Biotechnology, Govt. of India	PI
2024-2025	A novel biomarker screening for sensitivity in MSI cancers	Translational Research Exchange (TREX) Grant, National University of Singapore	PI
2023-2025	Screening for novel synthetic lethal targets in Arid1a deficient cancers	Open Fund Young Investigator Research (OF-YIRG) Grant, National Medical Research Council, Govt. of Singapore	PI

CV

Education:

Year	Degree	Institute
2015	Ph. D	Texas A&M University, College Station, USA
2008	M. Tech	Indian Institute of Technology, Roorkee, India
2005	B. Tech	Government Engineering College, Trichur, India

Research Experience:

Year	Title	Institute
07/2025-Present	Ramalingaswami Re-entry Fellow	National Institute of Biomedical Genomics Kalyani, BRIC-NIBMG, India
05/2022-06/2025	Special Fellow	Cancer Science Institute of Singapore, National University of Singapore, Singapore
03/2025-12/2020	Postdoctoral Fellow	Laboratory of Genome Integrity, National Institutes of Health, Bethesda, USA

Talks and Posters:

2024	“Chromatin reorganization under replication stress” Chromatin Stability 2024	Poster
2024	“Chromatin remodeling at replication forks to counteract replication stress” EMBO Workshop on The DNA-damage response in cell physiology and disease	Talk
2024	“Chromatin reorganization under replication stress” EMBO Workshop on Chromatin Biology in Cancer	Poster
2024	“Replication Stress and Genome Instability.” Manipal School of Life Sciences	Talk
2024	“Chromatin reorganization under replication stress” EMBO Workshop on Evolution and diversity of the DNA damage response	Poster
2023	“Simple Tandem Repeats (STRs) as a source of replication stress and genome instability.” Duke-NUS Medical School	Talk
2022	N2CR Seminar Series National University of Singapore	Talk
2021	“Genomic signatures underlying DNA replication stress and its clinical relevance.” Manipal School of Life Sciences	Talk
2019	“High resolution mapping to ascertain sites of replication fork reversal genome-wide.” CSHL Meeting: Eukaryotic DNA Replication & Genome Maintenance	Poster
2019	“Landscape of replication Stress Induced DNA Damage” Keystone Meeting: DNA Replication and Genome Instability: From Mechanism to Disease	Talk

Publications

For a complete list of publications please visit Google Scholar Profile

Lab members

1) Anwesha Panda (iPhD student)

Join Our Lab

We are always on the lookout for highly motivated and passionate researchers to join our team! If you have a strong background in molecular biology, life sciences or genomics, and are excited about pursuing interdisciplinary research at the interface of cell biology, DNA replication, and genome stability, we would love to hear from you.

We welcome inquiries from:

iPhD / PhD candidates

Master’s students

Bachelor’s students

Before reaching out, we encourage you to explore our recent publications to learn more about our research focus and approach.

If you are interested in joining us, please send an email to ss16@nibmg.ac.in with your CV and a brief statement about your research interests.