Melike Caglayan, PhD

Associate Professor, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center
Full member, Fred & Pamela Buffett Cancer Center
Research focus: Genome stability, DNA damage, DNA repair, DNA replication, biochemistry, X-ray crystallography, single-molecule biophysics

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Phone: 402-559-6153

Research

The Caglayan laboratory investigates the molecular mechanisms of DNA repair, particularly the base excision repair (BER), and how defects in DNA damage processing contribute to genome instability and cancer development. A central focus of Dr. Caglayan’s research program is to elucidate how human DNA ligase 1 (LIG1) and DNA ligase 3α (LIG3α) ensure high fidelity during the final DNA ligation step of the repair process, thereby maintaining genome integrity.

Using an integrated approach that combines biochemistry, X-ray crystallography, and biophysical methods, the lab aims to bridge the knowledge gap between DNA damage and human disease, with the long-term goal of informing strategies for treatment and prevention.

For information on student rotation opportunities please contact Dr. Caglayan at mcaglayan@unmc.edu

Research

Biochemical studies in the Caglayan laboratory have revealed that uncoordinated repair pathways at the final DNA ligation step can promote genome instability. Key discoveries include demonstrating how oxidative stress disrupts DNA ligase activity, leading to mutagenic outcomes. Dr. Caglayan’s work showed that the insertion of oxidized nucleotides generates repair intermediates that DNA ligases cannot efficiently join, providing the first evidence that the final nick-sealing step is compromised by oxidative DNA damage. The team also demonstrated how an identity of mismatch and ribonucleotides being inserted by DNA polymerase could impact the fidelity of DNA ligation by LIG1 and LIG3α at the final step of DNA repair pathway.

Using X-ray crystallography, the team has solved high-resolution structures of LIG1, providing atomic-level insights into how the ligase active site discriminates between correct and incorrect repair products, including mismatches, oxidative lesions, and aberrant sugar moieties. These structural studies further explain how disease-associated ligase mutations increase cancer susceptibility by permitting the ligation of mutagenic DNA intermediates.

In addition, the laboratory employs multi-color Total Internal Reflection Fluorescence (TIRF) microscopy and C-trap optical tweezers to visualize the dynamics of DNA replication and repair protein complexes at the single-molecule level. The team discovered how LIG1 search for broken DNA strand breaks to bind efficiently to maintain genome, enabling real-time analysis of DNA ligase function during damage repair.

Together, these studies provide critical molecular insights into how environmental toxins and oxidative stress compromise genome integrity, highlighting potential therapeutic targets for cancer prevention and treatment.

Selected Publications

Nucleic Acids Research

1. Balu K., Almahdor D., Lerner C., Ratcliffe J., Tang Q., Parwal T., Prakash A., Çağlayan M. (2025) Processing of DNA strand breaks with oxidatively damaged ends by LIG1. Nucleic Acids Research. 53: gkaf1344.

2. Ratcliffe J., Lerner C., Balu K., Chatterjee S., Lee K.M., Çağlayan M. (2025) Impaired nick recognition and ligation efficiency by LIG1 K845N variant linked to Huntington’s Disease. Nucleic Acids Research Molecular Medicine – Special Collection: Repat Expansion Diseases. 2: ugaf038.

3. Chatterjee S., Chaubet L., Berg A., Mukhortava A., Almohdar D., Ratcliffe J., Gulkis M., Çağlayan M. (2024) Probing nick DNA binding by LIG1 at the single-molecule level. Nucleic Acids Research. 52: 12604-12615.

4. Gulkis M., Martinez E., Almohdar D., Çağlayan M. (2024) Unfilled gaps by polβ leads to aberrant ligation by LIG1 at the downstream steps of base excision repair. Nucleic Acids Research. 52: 3810-3822.

5. Çağlayan M. (2020) The ligation of polβ mismatch insertion products governs the formation of promutagenic base excision DNA repair intermediates. Nucleic Acids Research 8: 3708-3721.

6. Çağlayan M., Prasad R., Krasich R., Longley M.J., Kadoda K., Tsuda M., Sasanuma H., Takeda S., Tano K., Copeland W.C., Wilson S.H. (2017) Complementation of aprataxin deficiency by base excision repair enzymes in mitochondrial extracts. Nucleic Acids Research 17: 10079-10088.

7. Çağlayan M., Horton J.K., Prasad R., Wilson S.H. (2015) Complementation of aprataxin deficiency by base excision repair enzymes. Nucleic Acids Research 43: 2271-2281.

Journal of Biological Chemistry

8. Lee K.M., Castro E., Ratcliffe J., Lerner C., Çağlayan M. (2025) Nick sealing of polβ mismatch insertion products by LIG1 and LIG3α during 8-oxoG bypass leads to mutagenic or error-free base excision repair pathway. Journal of Biological Chemistry. 6: 108540.

9. Balu K., Almohdar D., Tang Q., Ratcliffe J., Kalaycioglu M., Çağlayan M. (2024) Structures of LIG1 uncover the mechanism of sugar discrimination against 5'-RNA-DNA junctions during ribonucleotide excision repair. Journal of Biological Chemistry. 9: 107688.

10. Almohdar D., Murcia M., Tang Q., Ortiz A., Martinez E., Parwal, T., Kamble P., Çağlayan M. (2024) Impact of DNA ligase 1 and IIIα interactions with APE1 and polβ on the efficiency of base excision repair pathway at the downstream steps. Journal of Biological Chemistry. 300: 107355.

11. Balu K., Gulkis M., Almohdar D., Çağlayan M. (2024) Structures of LIG1 provide a mechanistic basis for understanding a lack of sugar discrimination against a ribonucleotide at the 3'-end of nick DNA. Journal of Biological Chemistry. 300: 107216.

12. Tang Q. and Çağlayan M. (2021) The scaffold protein XRCC1 stabilizes the formation of polβ/gap DNA and ligase IIIα/nick DNA complexes in base excision repair. Journal of Biological Chemistry 297: 101025.

13. Kamble P., Hall K., Chandak M., Tang Q., Çağlayan M. (2021) DNA ligase I fidelity the mutagenic ligation of pol β oxidized and mismatch nucleotide insertion products in base excision repair. Journal of Biological Chemistry 296: 100427.

Nature Communications

14. Tang Q., Gulkis M., McKenna R., Çağlayan M. (2022) Structures of LIG1 that engage with mutagenic mismatches inserted by polβ in base excision repair. Nature Communications 13: 3860.

15. Çağlayan M*. and Wilson S.H. (2018) Pol μ dGTP mismatch insertion opposite T coupled with ligation reveals a promutagenic DNA intermediate during double strand break repair. Nature Communications 9: 4213. *Co-corresponding author

16. Çağlayan M., Horton J.K., Da-Peng D., Stefanick D.F., Wilson S.H. (2017) Oxidized nucleotide insertion by pol β confounds ligation during base excision repair. Nature Communications 8: 14045.

17. Çağlayan M., Batra V.K., Sassa A., Prasad R., Wilson S.H. (2014) Role of polymerase β in complementing aprataxin deficiency during abasic-site base excision repair. Nature Structural and Molecular Biology 21: 497-499.

Appointments, Awards and Grants

Appointments:

2025 - present: Associate Professor, Eppley Institute, University of Nebraska Medical Center
2019 - 2025: Assistant Professor, Department of Biochemistry, College of Medicine, University of Florida
2013 - 2018: Postdoctoral Fellow, National Institute of Environmental Health Science (NIEHS)/NIH

Honors & Awards:

2024: UF Health Cancer Center Rising Star of the Year Award
2022: ASBMB Early Career Award
2020: UF College of Medicine Thomas H. Maren Junior Investigator Award
2019: EMGS Young Scientist Award
2015: NIH Pathway to Independence Award K99/R00