HSP110 translocates to the nucleus upon genotoxic chemotherapy and promotes DNA repair in colorectal cancer cells
Sébastien Causse
(1, 2, 3)
,
Guillaume Marcion
(1, 2, 3)
,
Gaëtan Chanteloup
(1, 2, 3)
,
Burhan Uyanik
(1, 2, 3)
,
Christophe Boudesco
(1, 2, 3)
,
Bogdan Grigorash
(1, 2, 3)
,
Romain Douhard
(1, 2, 3)
,
Alexandre Dias
(1, 2, 3)
,
Baptiste Dumetier
(1, 2, 3)
,
Lucile Dondaine
(1, 2, 3)
,
Gustavo Gozzi
(1, 2, 3)
,
Etienne Moussay
(4)
,
Jérôme Paggetti
(4)
,
Céline Mirjolet
(5)
,
Aurélie de Thonel
(6)
,
Laurence Dubrez
(1, 2, 3)
,
Oleg Demidov
(1, 2, 3)
,
Jessica Gobbo
(1, 2, 3, 5)
,
Carmen Garrido
(1, 2, 3, 5)
1
LNC -
Lipides - Nutrition - Cancer [Dijon - U1231]
2 LabEx LipSTIC - Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer
3 UBFC - Université Bourgogne Franche-Comté [COMUE]
4 LIH - Luxembourg Institute of Health
5 UNICANCER/CRLCC-CGFL - Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon]
6 EDC - Centre épigénétique et destin cellulaire
2 LabEx LipSTIC - Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer
3 UBFC - Université Bourgogne Franche-Comté [COMUE]
4 LIH - Luxembourg Institute of Health
5 UNICANCER/CRLCC-CGFL - Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon]
6 EDC - Centre épigénétique et destin cellulaire
Céline Mirjolet
- Fonction : Auteur
- PersonId : 767828
- ORCID : 0000-0003-0047-9421
Laurence Dubrez
- Fonction : Auteur
- PersonId : 183779
- IdHAL : laurence-dubrez-daloz
- ORCID : 0000-0002-7030-2181
- IdRef : 133798194
Jessica Gobbo
- Fonction : Auteur
Carmen Garrido
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- Fonction : Auteur correspondant
- PersonId : 992766
- ORCID : 0000-0003-1368-1493
- IdRef : 095167196
Connectez-vous pour contacter l'auteur
Résumé
A multicenter clinical study demonstrated the presence of a loss-of-function HSP110 mutation in about 15% of colorectal cancers, which resulted from an alternative splicing and was produced at the detriment of wild-type HSP110. Patients expressing low levels of wild-type HSP110 had excellent outcomes (i.e. response to an oxaliplatin-based chemotherapy). Here, we show in vitro, in vivo, and in patients' biopsies that HSP110 co-localizes with DNA damage (γ-H2AX). In colorectal cancer cells, HSP110 translocates into the nucleus upon treatment with genotoxic chemotherapy such as oxaliplatin. Furthermore, we show that HSP110 interacts with the Ku70/Ku80 heterodimer, an essential element of the non-homologous end joining (NHEJ) repair machinery. We also demonstrate by evaluating the resolved 53BP1 foci that depletion in HSP110 impairs repair steps of the NHEJ pathway, which is associated with an increase in DNA double-strand breaks and in the cells' sensitivity to oxaliplatin. HSP110-depleted cells sensitization to oxaliplatin-induced DNA damage is abolished upon re-expression of HSP110. Confirming a role for HSP110 in DNA non-homologous repair, SCR7 and NU7026, two inhibitors of the NHEJ pathway, circumvents HSP110-induced resistance to chemotherapy. In conclusion, HSP110 through its interaction with the Ku70/80 heterodimer may participate in DNA repair, thereby inducing a protection against genotoxic therapy.