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It undergoes antigenic variation and sequentially expresses distinct VSGs, its major surface antigen, thereby effectively evading the host\u2019s immune response. We have shown that many telomere proteins suppress VSG switching, as VSGs are expressed exclusively from subtelomeric loci. We have now identified the\n                      <jats:italic toggle=\"yes\">T. brucei<\/jats:italic>\n                      TEL2 homolog based on its sequence and predicted structure similarities to those of known TEL2 homologs. TEL2 homologs have a conserved function of maintaining the protein stability of PI3K-related protein kinases (PIKKs). Interestingly,\n                      <jats:italic toggle=\"yes\">Tb<\/jats:italic>\n                      TEL2 maintains the stability of\n                      <jats:italic toggle=\"yes\">Tb<\/jats:italic>\n                      ATR and most other PIKK proteins by protecting them from the 26S proteasome-mediated degradation. This is different from mechanisms revealed in mammals and fission yeast, where TEL2 homologs act as an HSP90 co-chaperone and ensure co-translational maturation of PIKKs. In addition,\n                      <jats:italic toggle=\"yes\">Tb<\/jats:italic>\n                      TEL2 is essential for genome integrity and acts as another critical player in antigenic variation regulation. More DNA breaks have been detected at multiple\n                      <jats:italic toggle=\"yes\">T. brucei<\/jats:italic>\n                      loci, including both active and silent subtelomeric VSG expression sites in\n                      <jats:italic toggle=\"yes\">Tb<\/jats:italic>\n                      TEL2-depleted cells. Furthermore, a transient depletion of\n                      <jats:italic toggle=\"yes\">Tb<\/jats:italic>\n                      TEL2 leads to a significant increase in the number of VSG switching events via DNA recombination-mediated and transcriptional switching pathways. Hence, the increased genome instability promotes antigenic variation potential. However, only a trace amount of \u03b3H2A, a marker of DNA damage, was detected transiently upon\n                      <jats:italic toggle=\"yes\">Tb<\/jats:italic>\n                      TEL2 depletion, presumably due to the diminution of H2A kinases in these cells, suggesting that persistent ATM\/ATR-mediated damage signaling is not essential for the increase in VSG switching rate.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        <jats:italic toggle=\"yes\">Trypanosoma brucei<\/jats:italic>\n                        causes sleeping sickness in humans and nagana in cattle, causing a severe economic burden in sub-Sahara Africa. Antigenic variation is a key pathogenesis mechanism that enables long-term parasitic infections and renders vaccination ineffective. We have identified\n                        <jats:italic toggle=\"yes\">T. brucei<\/jats:italic>\n                        TEL2 and shown that it is indispensable for parasite proliferation, essential for genome integrity, and critical for the regulation of antigenic variation. Importantly,\n                        <jats:italic toggle=\"yes\">Tb<\/jats:italic>\n                        TEL2 maintains the stability of PIKK proteins that are key players in various important cellular processes, indicating that\n                        <jats:italic toggle=\"yes\">Tb<\/jats:italic>\n                        TEL2 is a central regulator essential for parasite survival in its mammalian host. Importantly, we found that\n                        <jats:italic toggle=\"yes\">Tb<\/jats:italic>\n                        TEL2 protects PIKKs from the 26S proteasome-mediated protein degradation. This is distinct from the scenarios in mammals and fission yeast, where TEL2 homologs act as an HSP90 co-chaperone and ensure co-translational maturation of PIKKs. Characterizing the parasite\u2019s essential processes with unique mechanisms will help eventual eradication of\n                        <jats:italic toggle=\"yes\">T. brucei<\/jats:italic>\n                        infections.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.03516-25","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T22:39:21Z","timestamp":1780094361000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["<i>Trypanosoma brucei<\/i>\n                    TEL2 inhibits VSG switching and protects PIKKs from the 26S proteasome-mediated degradation"],"prefix":"10.1128","volume":"14","author":[{"given":"SK Abdus","family":"Sayeed","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/002tx1f22","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Gene Regulation in 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