Objective
The function of the well-known mismatch repair (MMR) is to correct mispairs and misalignments arising during DNA replication. Canonical MMR is dependent on MutLa, a nuclease consisting of MLH1 and PMS2 subunits. In addition to MutLa, human cells also contain the MutLg (MLH1-MLH3) nuclease, implicated in pathological trinucleotide repeat expansion and the processing of meiotic DNA recombination intermediates. Despite the biological and clinical importance of MutLg, its involvement in these processes remains poorly understood.
In Aim I, we will elucidate how MutLg and co-factors recognize and process secondary DNA structures formed within repetitive trinucleotide sequences to understand repeat expansion and protective mechanisms. In Aim II, we will define the functional role of MutLg and co-factors in resolving meiotic recombination intermediates, specifically how they cleave DNA structures such as Holliday junctions to yield crossover recombination products.
Our preliminary data indicate that the non-canonical MMR complexes dependent on MutLg are regulated very differently compared to the classical MMR factors, both in terms of the secondary DNA structures and the protein co-factors involved. The unexpected diversity of the regulatory mechanisms will offer exciting insights into how the various MMR complexes adapted to carry out distinct cellular functions in very different physiological contexts. We will employ robust biochemical reconstitution strategies, combined with advanced single-molecule imaging, enabling direct visualization of MutLg interactions and activity in real-time. Our approach overcomes previous technical barriers through optimized production of recombinant MutLg and specialized DNA substrates. By clarifying the mechanisms underlying MutLg’s diverse roles, this project will advance our understanding of fundamental biological processes and provide potential prospects for targeted treatment for Huntigton's and related disorders.
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Keywords
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
MAIN PROGRAMME
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Topic(s)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-ERC - HORIZON ERC Grants
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Call for proposal
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Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) ERC-2025-ADG
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6500 Bellinzona
Switzerland
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