TY - JOUR
T1 - Functional impact of titin (TTN) mutations in ocular surface squamous neoplasia
AU - Djulbegovic, Mak B.
AU - Uversky, Vladimir N.
AU - Karp, Carol L.
AU - Harbour, J. William
N1 - Funding Information:
NIH Center Core Grant P30EY014801, RPB Unrestricted Award, Dr. Ronald and Alicia Lepke Grant, The Lee and Claire Hager Grant, The Robert Farr Family Grant, The Grant and Diana Stanton-Thornbrough, The Robert Baer Family Grant, The Roberto and Antonia Menendez Grant, The Emilyn Page and Mark Feldberg Grant, The Calvin and Flavia Oak Support Fund, The Robert Farr Family Grant, The Jose Ferreira de Melo Grant, The Richard and Kathy Lesser Grant, The Honorable A. Jay Cristol Grant, The Michele and Ted Kaplan Grant and the Richard Azar Family Grant(institutional grants).
Publisher Copyright:
© 2021
PY - 2022/1/15
Y1 - 2022/1/15
N2 - Mutations in the titin (TTN) gene are among the most common genomic aberrations in ocular surface squamous neoplasia (OSSN), the most common cancer of the external eye. Further, TTN mutations are associated with resistance to standard therapy with topical interferon alpha-2b (IFN-α2b). However, it remains unclear how TTN mutations drive OSSN pathogenesis and treatment resistance. TTN encodes the largest protein in the human body and its best understood function is as a myofibril scaffold in striated muscle. However, recent evidence indicates that TTN has additional functions in non-muscle cells and in cancer. Here, we performed a disorder-based bioinformatics analysis which revealed that intrinsically disordered protein regions are abundant in TTN and provide mechanistic insights into its function as a nuclear protein in epithelial cells. Specific mutations found in OSSN are predicted to affect its intrinsically disordered protein regions (IDPRs), promoting chromosomal instability, oncogenesis, and altered response to IFN-α2b treatment.
AB - Mutations in the titin (TTN) gene are among the most common genomic aberrations in ocular surface squamous neoplasia (OSSN), the most common cancer of the external eye. Further, TTN mutations are associated with resistance to standard therapy with topical interferon alpha-2b (IFN-α2b). However, it remains unclear how TTN mutations drive OSSN pathogenesis and treatment resistance. TTN encodes the largest protein in the human body and its best understood function is as a myofibril scaffold in striated muscle. However, recent evidence indicates that TTN has additional functions in non-muscle cells and in cancer. Here, we performed a disorder-based bioinformatics analysis which revealed that intrinsically disordered protein regions are abundant in TTN and provide mechanistic insights into its function as a nuclear protein in epithelial cells. Specific mutations found in OSSN are predicted to affect its intrinsically disordered protein regions (IDPRs), promoting chromosomal instability, oncogenesis, and altered response to IFN-α2b treatment.
KW - Interferon alpha-2b
KW - Intrinsic disorder
KW - Ocular surface squamous neoplasia
KW - Titin
UR - http://www.scopus.com/inward/record.url?scp=85120915790&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85120915790&partnerID=8YFLogxK
U2 - 10.1016/j.ijbiomac.2021.11.120
DO - 10.1016/j.ijbiomac.2021.11.120
M3 - Article
C2 - 34838574
AN - SCOPUS:85120915790
SN - 0141-8130
VL - 195
SP - 93
EP - 101
JO - International Journal of Biological Macromolecules
JF - International Journal of Biological Macromolecules
ER -