Translation control of autophagy genes modulates cellular response to hydroxyurea-induced genotoxic stress

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Abstract
The fine balance between cellular homeostasis and stress response is crucial for cell survival under conditions of genotoxic stress. Here, we identify a regulatory role for the translation repressor Sbp1 in modulating autophagy during hydroxyurea (HU)-induced replication stress. We observe that Sbp1 localizes to reversible, mRNA-containing cytoplasmic granules specifically upon HU treatment in an RGG motif-dependent manner. Loss of Sbp1 leads to selective translational upregulation of key autophagy genes ATG1, ATG2, and ATG9. Consistent with these translational changes, sbp1∆ cells exhibit increased selective macroautophagy/autophagy and enhanced bulk autophagy, whereas Sbp1 overexpression suppresses both processes. Interestingly, overexpression of Sbp1 shifts DNA repair toward non-homologous end joining (NHEJ) repair, linking altered autophagy to genome maintenance. Together, these findings identify Sbp1 as a negative regulator of autophagy during replication stress and suggest a regulatory axis linking granule-mediated mRNA sequestration, translational control of autophagy factors, and the cellular response to genotoxic stress.Abbreviations: CHX: cycloheximide; CPT: camptothecin; DDR: DNA damage response; GTA: genotoxin-associated targeted autophagy; HR: homologous recombination; HU: hydroxyurea; MMS: methyl methanesulfonate; mRNPs: mRNA-protein complexes; NHEJ: non-homologous end joining; P-bodies: processing bodies; RBPs: RNA binding proteins.
Funding Information
  • Indo-French Centre for the Promotion of Advanced Research (7003-H/7003-2)
  • India Alliance DBT-Wellcome Trust (IA/I/12/2/)
  • Department of Biotechnology (DBT), Government of India (BT/PR51975/BMS/85/23/2024)
  • DST-FIST program
  • Ministry of Education, India
  • DBT, INDIA
  • Department of Biotechnology, Ministry of Science and Technology, India
  • Ministry of Education, India
  • Wellcome Trust DBT India Alliance (IA/I/12/2/500625)

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