Oral Presentation Inaugural Australian Ubiquitin Summit 2025

SOCS2 interacts with RNF169 in acute myeloid leukemia to regulate ubiquitination in the DNA damage response (129649)

Kunlun Li 1 2 , Rhiannon Morris 1 2 , Ashley Weir 1 2 , Laura Dagley 1 2 , Yuntong Wu 1 2 , Simon Cobbold 1 2 , Colin Hockings 1 2 , Steve Binos 1 2 , Grace Bidgood 1 2 , Cyrus Tan 1 2 , Ruth Cuzzupe 1 2 , Brad Sleebs 1 2 , Nadia Davidson 1 2 , Andrew Wei 1 2 , David Komander 1 2 , Nadia Kershaw 1 2 , Jeff Babon 1 2 , Sandra Nicholson 1 2
  1. The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
  2. Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia

Acute myeloid leukemia (AML) is a highly-resistant and aggressive blood cancer with a five-year survival rate of <30%. Suppressor of cytokine signalling (SOCS)2 is an SH2-containing substrate receptor for the Cullin-5 RING E3 ligase (CRL5) complex. High SOCS2 expression correlates with poor prognosis in AML, with evidence that it regulates the hematopoietic stem cell pool and enables AML development. The SOCS2 mechanism of action in AML is not known.
Here we identified the DNA repair protein and putative E3 ligase RNF169 as a novel binder for an allosteric site on the SOCS2-SH2 domain. Cross-linking/mass spectrometry revealed that both RNF169 and Cullin-5 are complexed with SOCS2. Several DNA damage repair proteins were also identified that interacted with SOCS2 in a pTyr-dependent manner, with binding enhanced in the presence of RNF169. Profiling of global changes in ubiquitination following DNA damage in SOCS2-null AML cells revealed widespread reduction in ubiquitination of proteins involved in non-homologous end joining (NEJ) and nucleotide excision repair.
Functionally, loss of SOCS2 augmented G2M cell cycle arrest in response to ionizing irradiation. Conversely, increasing SOCS2 levels to mimic “high” SOCS2 in patient AML, increased cell cycle transit and was associated with enhanced RNF169 binding to DNA damage foci. Interestingly, this did not trigger increased cell death, suggesting greater tolerance of defective DNA repair.
This is the first report of SOCS2 regulating the DNA damage response and predicts that inhibition of SOCS2 and/or blocking the SOCS2:RNF169 interaction should be explored as a treatment strategy following DNA-damage inducing therapies.