Dr Alex Garvin

Introduction

The conjugation of SUMOs (Small Ubiquitin-like Modifiers) to lysine residues (SUMOylation) is a post-translational modification similar to ubiquitination, although it is far less well understood. SUMOylation plays pervasive roles in cell signalling, impacting fundamental cellular processes including transcription, DNA replication, chromatin remodelling, immunity, development, and genome stability. Dysregulation of SUMOylation is implicated in a broad range of human diseases, with SUMOylation inhibitors showing promise in early-stage clinical trials against cancer. As a modification, SUMOylation is highly dynamic, often occurring as transient spikes in response to stress insults or specific cellular cues. A key feature of this dynamic regulation is the action of deSUMOylating proteases, including SENPs (Sentrin/SUMO-specific proteases). Despite thousands of SUMOylation events being mapped to hundreds of proteins, the removal of SUMOs is carried out by fewer than a dozen enzymes. How these enzymes are regulated and dysregulated in health and disease is a primary research focus of my lab.

Current major projects

• The role of chain editing SENP enzymes in genome stability.
• Role of SENP amplification in Lung Squamous Cell Carcinoma (LUSC)
• Function of an atypical “pseudoSUMO” in human health.
• SENP enzyme specificity and targeting.

Detailed research programme

The role of chain editing SENP enzymes in genome stability

Similar to ubiquitin, SUMOs can conjugate to themselves, forming polymeric chains attached to substrates. PolySUMOs vary in length and composition, incorporating ubiquitin and other ubiquitin-like modifiers such as NEDD8. These polymers can also form on all eight internal SUMO lysines, which collectively massively increase the complexity of the SUMO signalling code. Specialised SUMO writers, readers, and erasers act on polySUMO, including two chain-editing SENPs (SENP6 and SENP7). I have previously demonstrated that SENP7 is a chromatin-resident deSUMOylase that plays essential roles in SUMO-dependent chromatin relaxation, required for the efficient repair of DNA double-strand breaks (DSBs) (Garvin et al. 2013 EMBO Reports DOI: 10.1038/embor.2013.141). Building on these findings, by using a mouse model of disrupted Senp7 expression, we are investigating additional features of SENP7 related to its function in maintaining genome stability. Alongside these cellular phenotyping assays, we are exploring how SENP7 targets its substrates for deSUMOylation.

Role of SENP amplification in Lung Squamous Cell Carcinoma

Unbalanced SUMOylation is prevalent in many cancer types, most likely arising from persistent stress signalling. An “addiction” to SUMOylation has also been reported in c-myc driven cancers, indicating that SUMO enzymes represent promising future therapeutic targets. Of the six SENP proteases, three are located on the q arm of chromosome 3 (3q). Copy number amplification of 3q is one of the most common but least understood chromosomal abnormalities in epithelial cancers of the lung, cervix, ovaries, and oesophagus. In previous work, I demonstrated that SENP2, one of the 3q amplified SENPs, is vital for DSB repair, and that amplification of SENP2 alters sensitivity to different types of DNA-damaging chemotherapy (Garvin et al 2019. Genes and Development DOI: 10.1101/gad.321125.118). We are currently focusing on Lung Squamous Cell Carcinoma (LUSC), in which approximately 40% of patients carry the 3q amplification. LUSC patients have a particularly poor survival rate, and at present, there are no molecular targeted therapies available for treatment. This work is funded by an Academy of Medical Sciences Springboard award and aims to determine if SENPs represent a therapeutic vulnerability that can be exploited for the treatment of LUSC.

Function of an atypical “pseudoSUMO” in human health

 SUMOs are a family of related proteins (SUMO1-5); SUMO1-3 are well characterised, while SUMO5 may be a pseudogene. SUMO4, despite being first identified many years ago, has remained functionally elusive. SUMO4 differs from other SUMOs in its inability to be conjugated, leading to the assumption that it is non-functional. For the first time, I was able to demonstrate that SUMO4 functions as an atypical family member – signalling as a free SUMO rather than forming conjugates. SUMO4 instead acts as a buffer to SUMO1-3 conjugation by regulating the activity of SENP1. Therefore, SUMO4 and SENP1 work together to control SUMOylation levels in DSB signalling (Garvin et al. 2025 Molecular Cell DOI: 10.1016/j.molcel.2025.02.004). Having lost a major function of SUMOs (conjugation) but retained sufficient homology to interact with the SUMO conjugation/deconjugation machinery, I refer to SUMO4 as a psuedoSUMO, analogous to pseudokinases. We are currently expanding on this work:

• To understand the molecular mechanism by which SUMO4 stimulates SENP1 protease activity.
• The impact of SUMO4 polymorphisms on cellular function in a variety of signalling pathways.
• Improved methods of detecting endogenous SUMO4, as commercially available antibodies are cross-reactive with SUMO2/3 (Garvin et al. 2022 Scientific Reports DOI: 10.1038/s41598-022-25665-6).

SENP enzyme specificity and targeting

Our understanding of how SENPs specifically target certain subsets of substrates remains limited. Alongside Elton Zeqiraj, we are purifying SENP enzymes with boundaries that encompass adjacent, uncharacterised domains and regions, which may illuminate how specificity is achieved with SENPs. We are also working towards identifying novel SENP binders and modulators as affinity reagents and to tune their function.