TY - JOUR
T1 - Characterization of the role of Fhit in suppression of DNA damage
AU - Saldivar, Joshua C.
AU - Bene, Jessica
AU - Hosseini, Seyed Ali
AU - Miuma, Satoshi
AU - Horton, Susan
AU - Heerema, Nyla A.
AU - Huebner, Kay
N1 - Funding Information:
We thank members of the Huebner lab for helpful discussions. This work was supported by grants from the National Institutes of Health, USPHS to KH ( CA120516 , CA132453 , CA115965 ) and to JCS ( F31CA157150 , T32GM068412 ).
PY - 2013/1
Y1 - 2013/1
N2 - The fragile histidine triad protein, Fhit, has a number of reported tumor suppressive functions which include signaling of apoptosis in cancer cells in vitro and in vivo, modulation of the DNA damage response, down-regulation of target oncogene expression, suppression of tumor growth in vivo, and suppression of cancer cell invasion and metastasis. Most of these functions of Fhit have been observed on exogenous re-expression of Fhit in Fhit-negative cancer cells. However, little is known about the tumorigenic changes that occur in normal or precancerous cells following loss of Fhit expression. Recently, we have shown that shortly after loss of Fhit expression, cells exhibit signs of DNA replication stress-induced DNA damage and develop genomic instability. Here, we extend these findings through investigation of different factors that affect Fhit function to prevent DNA damage. We found that Fhit activity is dependent upon a functional HIT domain and the tyrosine-114 residue, previously shown to be required for tumor suppression by Fhit. Furthermore, Fhit function was shown to be independent of exogenous and endogenous sources of oxidative stress. Finally, Fhit function was shown to be dependent upon Chk1 kinase activity, but independent of Atr or Atm kinases. Evidence suggests that Fhit and Chk1 kinase cooperate to prevent replication stress-induced DNA damage. These findings provide important and unexpected insights into the mechanism whereby loss of Fhit expression contributes to cell transformation.
AB - The fragile histidine triad protein, Fhit, has a number of reported tumor suppressive functions which include signaling of apoptosis in cancer cells in vitro and in vivo, modulation of the DNA damage response, down-regulation of target oncogene expression, suppression of tumor growth in vivo, and suppression of cancer cell invasion and metastasis. Most of these functions of Fhit have been observed on exogenous re-expression of Fhit in Fhit-negative cancer cells. However, little is known about the tumorigenic changes that occur in normal or precancerous cells following loss of Fhit expression. Recently, we have shown that shortly after loss of Fhit expression, cells exhibit signs of DNA replication stress-induced DNA damage and develop genomic instability. Here, we extend these findings through investigation of different factors that affect Fhit function to prevent DNA damage. We found that Fhit activity is dependent upon a functional HIT domain and the tyrosine-114 residue, previously shown to be required for tumor suppression by Fhit. Furthermore, Fhit function was shown to be independent of exogenous and endogenous sources of oxidative stress. Finally, Fhit function was shown to be dependent upon Chk1 kinase activity, but independent of Atr or Atm kinases. Evidence suggests that Fhit and Chk1 kinase cooperate to prevent replication stress-induced DNA damage. These findings provide important and unexpected insights into the mechanism whereby loss of Fhit expression contributes to cell transformation.
UR - http://www.scopus.com/inward/record.url?scp=84874005557&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84874005557&partnerID=8YFLogxK
U2 - 10.1016/j.jbior.2012.10.003
DO - 10.1016/j.jbior.2012.10.003
M3 - Article
C2 - 23102829
AN - SCOPUS:84874005557
SN - 2212-4926
VL - 53
SP - 77
EP - 85
JO - Advances in Biological Regulation
JF - Advances in Biological Regulation
IS - 1
ER -