Lysine Methylation and DNA Damage Group

Group leader: Dr Martin Higgs

Overview

Efficient and accurate repair of DNA damage is vital to protect the genome, and prevent cancer development. Our research focuses on understanding how DNA repair is regulated, and how problems with this process contribute to inherited human disease and cancer.   

Our research group

The gradual accumulation of genome damage is a fundamental factor in the transformation of healthy cells into tumour cells. To counteract this, cells have evolved complex networks of proteins which allow the recognition and repair of damaged DNA. These factors collectively form the ‘DNA damage response’ (DDR), and constitute an important barrier to the prevention of human disease. Deficiencies in this response contribute to the development of cancer, as well as underlying several rare inherited human syndromes.

KMT DDR logo

The proteins involved in the DDR are regulated by an intricate series of modifications, which function to regulate their abilities to appropriately detect/repair damaged DNA. One such modification is Lys methylation, which is carried out by a specific set of enzymes known as Lys methyltransferases (KMTs). The Lysine Methylation and DNA Damage group explores how DDR factors are regulated through Lys methylation, and how KMTs themselves are regulated.

As well as studying how Lys methylation plays a role in DNA repair, a large proportion of the research ongoing in the group http://www.birmingham.ac.uk/research/activity/mds/centres/genome-biology/index.aspxcentres around understanding how defects in Lysine methylation contribute to rare inherited human disorders, especially those characterised by elevated genome instability.

Projects in the lab are funded by the MRC, Wellcome Trust, and the University of Birmingham.

Current projects

  1. Understanding how lysine methylation controls the repair of DNA damage.
  2. Studying how deficiencies in lysine methyltransferases are involved in inherited human disease.
  3. Identifying novel epigenetic factors and methyltransferases involved in the DDR.
  4. Examining how lysine methyltransferases are regulated, in particular by post-translational modifications.
  5. Understanding how viruses subvert host cell DNA damage response pathways, especially the impact on lysine methyltransferases.

Recent publications

  • 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†. Histone methylation by SETD1A protects nascent DNA through the nucleosome chaperone activity of FANCD2. Mol Cell. 2018 71(1):25-41. († co-corresponding author)

  • Reynolds JJ*, Bicknell LS*, Carroll P*, Higgs MR*, Shaheen R*, et al. Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism. Nature Genetics. 2017 49(4):537-549 (* joint first author).

  • Harley ME, Murina O, Leitch A, Higgs MR, Bicknell LS, et al. The primordial dwarfism gene TRAIP promotes DNA damage response during genome replication. Nature Genetics. 2016 48(1):36-43.
  • Higgs MR*, Reynolds JJ*, Winczura A, Blackford A,  Miller ES, Zlatanou N, Borel V, Niemenszyca J, Ryan EL, Davies N, Stankovic S, Boulton SJ, Niedzwiedz W, Stewart GS. BOD1L is required to suppress deleterious resection of stressed replication forks. Mol Cell. 2015 59(3):462-77. (* joint first author).
  • Kotsantis P, Jones RM, Higgs MR, Petermann E. Cancer therapy and replication stress: forks on the road to perdition. Advances in Clinical Chemistry. 2015 69:91-138.

For an up-to-date publication list, please see: https://scholar.google.co.uk/citations?user=P-JONyAAAAAJ&hl=en&oi=ao

Staff

Postdoctoral Fellows:

  • Dr. Rachel Bayley
  • Dr. Shabana Begum

Research Technician:

  • Amalia Goula