Investigating how novel targets of lysine methylation regulate DNA repair

Our DNA is under constant attack from genotoxic agents, which are a continuing threat to genomic integrity. Defective resolution of DNA damage underlies several human diseases, including neurological abnormalities and developmental disorders as well as cancer. To counteract this, multiple DNA damage response (DDR) proteins act to combat DNA damage, by detecting DNA damage, activating cell cycle checkpoints, and promoting the repair/resolution of DNA lesions. The activity of these factors is controlled by a complex network of post-translational modifications.

The Higgs lab focuses on one post-translational modification, lysine methylation, and the enzymes that catalyse this, known as ‘lysine methyltransferases’. These lysine methyltransferases play vital roles in maintaining human health and development, and in preventing tumourigenesis. Our main interest is on how these enzymes control DNA repair and therefore prevent genome instability.

This PhD will build on preliminary data that has identified multiple novel substrates of lysine methyltransferases, with the aim of characterising the impact on the DDR and on DNA repair. These substrates include scaffolds, nucleases, helicases and polymerases that play key roles in the response to DNA damage. Our hypothesis is that these modifications regulate their activity and/or ability to support effective DNA repair.

The project will involve a wide variety of laboratory techniques, including mass spectrometry, co-immunoprecipitation, CRISPR/Cas9 and RNAi techniques, in vitro activity and binding assays, fluorescent and visual microscopy, immunoblotting and immunofluorescence, molecular cloning, cell culture and in-depth DNA repair assays. The findings from this project will lead to a greater understanding of how lysine methylation is involved in promoting DNA repair, maintaining genome stability and preventing human disease.

Person specification: Applicants should have a strong background in molecular and cellular biology, with experience of the following laboratory techniques: mammalian tissue culture; immunofluorescence; immunoblotting or molecular cloning. Previous experience of a research lab environment is essential. They should be ambitious, enthusiastic and self-motivated, and hold at least an Upper Second Class Honours Degree in a relevant biological subject. They should also be able to demonstrate a high level of proficiency in the English language to the required level.

For further information, please contact m.r.higgs@bham.ac.uk.

Funding notes:

This PhD position is only open to self-funded PhD students or those that hold a relevant scholarship/funding.

You can search for relevant funding opportunities here: https://www.birmingham.ac.uk/study/international/fees/scholarships and https://www.birmingham.ac.uk/funding/postgraduate.

References:

SETD1A-dependent EME1 transcription drives PARPi sensitivity in HR deficient tumour cells. Sweatman E, Bayley R, Selemane R, Higgs MR. Br J Cancer. 2025 Feb 24. doi: 10.1038/s41416-025-02963-0.

H3K4 methylation by SETD1A/BOD1L facilitates RIF1-dependent NHEJ. Bayley R, Borel V, Moss RJ, Sweatman E, Ruis P, Ormrod A, Goula A, Mottram RMA, Stanage T, Hewitt G, Saponaro S, Stewart GS, Boulton SJ, Higgs MR. Mol Cell 2022 82(10): p 1924-1939 e10

SET1A-Mediated Mono-Methylation at K342 Regulates YAP Activation by Blocking Its Nuclear Export and Promotes Tumorigenesis. Fang L, Teng H, Wang Y, Liao G, Weng L, Li Y, Wang X, Jin J, Jiao C, Chen L, Peng X, Chen J, Yang Y, Fang H, Han D, Li C, Jin X, Zhang S, Liu Z, Liu M, Wei Q, Liao L, Ge X, Zhao B, Zhou D, Qin HL, Zhou J, Wang P. Cancer Cell. 2018 Jul 9;34(1):103-118.e9.

Histone methylation by SETD1A protects nascent DNA through the nucleosome chaperone activity of FANCD2. Higgs MR, Sato K, Reynolds JR, Begum S, Bayley R, Goula A, Vernet A, Paquin KL, Skalnik DG, Kobayashi W, Takata M, Howlett NG, Kurumizaka H, Kimura H, Stewart GS. Mol Cell 2018 71(1):25-41