Merkel cell carcinoma (MCC) is an aggressive neuroendocrine cancer of the skin with high rates of metastasis and mortality. Besides well-established factors including genetic mutations and UV-induced DNA damage in Merkel cell carcinogenesis, the recent discovery of the Merkel cell polyomavirus (MCPyV) has shed light on the viral etiology of MCC. In the current study, we provide novel evidence that MCPyV small T (sT) antigen induces the DNA damage response (DDR) pathway. Our data show that in human MCC cells, the presence of MCPyV is associated with hyperphosphorylation of histone H2AX, a marker for DNA damage. We observed that overexpression of MCPyV sT antigen induced the phosphorylation of histone H2AX as well as the activation of ataxia telangiectasia mutant (ATM), an upstream kinase important for H2AX phosphorylation. Moreover, we observed that MCPyV sT expression also induced the hyperphosphorylation of other ATM downstream molecules (including 53BP1 and CHK2) as well as the hypermethylation of histone 3 and histone 4. These findings disclose a novel link between MCPyV sT and the DDR pathway in MCC. Given that measurement of DDR is clinically useful for evaluating treatment response to radio- and chemotherapy, our findings warrant further investigation to evaluate the potential implications of this pathway for MCC management.

1.
Feng
H
,
Shuda
M
,
Chang
Y
,
Moore
PS
.
Clonal integration of a polyomavirus in human Merkel cell carcinoma
.
Science
.
2008
Feb
;
319
(
5866
):
1096
100
.
[PubMed]
0036-8075
2.
Verhaegen
ME
,
Mangelberger
D
,
Harms
PW
,
Vozheiko
TD
,
Weick
JW
,
Wilbert
DM
, et al
Merkel cell polyomavirus small T antigen is oncogenic in transgenic mice
.
J Invest Dermatol
.
2015
May
;
135
(
5
):
1415
24
.
[PubMed]
0022-202X
3.
Shuda
M
,
Chang
Y
,
Moore
PS
.
Merkel cell polyomavirus-positive Merkel cell carcinoma requires viral small T-antigen for cell proliferation
.
J Invest Dermatol
.
2014
May
;
134
(
5
):
1479
81
.
[PubMed]
0022-202X
4.
Shuda
M
,
Kwun
HJ
,
Feng
H
,
Chang
Y
,
Moore
PS
.
Human Merkel cell polyomavirus small T antigen is an oncoprotein targeting the 4E-BP1 translation regulator
.
J Clin Invest
.
2011
Sep
;
121
(
9
):
3623
34
.
[PubMed]
0021-9738
5.
Goh
G
,
Walradt
T
,
Markarov
V
,
Blom
A
,
Riaz
N
,
Doumani
R
, et al
Mutational landscape of MCPyV-positive and MCPyV-negative Merkel cell carcinomas with implications for immunotherapy
.
Oncotarget
.
2016
Jan
;
7
(
3
):
3403
15
.
[PubMed]
1949-2553
6.
Demetriou
SK
,
Ona-Vu
K
,
Sullivan
EM
,
Dong
TK
,
Hsu
SW
,
Oh
DH
.
Defective DNA repair and cell cycle arrest in cells expressing Merkel cell polyomavirus T antigen
.
Int J Cancer
.
2012
Oct
;
131
(
8
):
1818
27
.
[PubMed]
0020-7136
7.
Wong
SQ
,
Waldeck
K
,
Vergara
IA
,
Schröder
J
,
Madore
J
,
Wilmott
JS
, et al
Uv-associated mutations underlie the etiology of mcv-negative merkel cell carcinomas
.
Cancer Res
.
2015
Dec
;
75
(
24
):
5228
34
.
[PubMed]
0008-5472
8.
Marti
TM
,
Hefner
E
,
Feeney
L
,
Natale
V
,
Cleaver
JE
.
H2AX phosphorylation within the G1 phase after UV irradiation depends on nucleotide excision repair and not DNA double-strand breaks
.
Proc Natl Acad Sci USA
.
2006
Jun
;
103
(
26
):
9891
6
.
[PubMed]
0027-8424
9.
O’Connor
MJ
.
Targeting the DNA damage response in cancer
.
Mol Cell
.
2015
Nov
;
60
(
4
):
547
60
.
[PubMed]
1097-2765
10.
Gillespie
KA
,
Mehta
KP
,
Laimins
LA
,
Moody
CA
.
Human papillomaviruses recruit cellular DNA repair and homologous recombination factors to viral replication centers
.
J Virol
.
2012
Sep
;
86
(
17
):
9520
6
.
[PubMed]
0022-538X
11.
Moody
CA
,
Laimins
LA
.
Human papillomaviruses activate the ATM DNA damage pathway for viral genome amplification upon differentiation
.
PLoS Pathog
.
2009
Oct
;
5
(
10
):
e1000605
.
[PubMed]
1553-7366
12.
Hong
S
,
Dutta
A
,
Laimins
LA
.
The acetyltransferase Tip60 is a critical regulator of the differentiation-dependent amplification of human papillomaviruses
.
J Virol
.
2015
Apr
;
89
(
8
):
4668
75
.
[PubMed]
0022-538X
13.
Urso
C
,
Pierucci
F
,
Sollai
M
,
Arvia
R
,
Massi
D
,
Zakrzewska
K
.
Detection of Merkel cell polyomavirus and human papillomavirus DNA in porocarcinoma
.
J Clin Virol
.
2016
May
;
78
:
71
3
.
[PubMed]
1386-6532
14.
Zannini
L
,
Delia
D
,
Buscemi
G
.
CHK2 kinase in the DNA damage response and beyond
.
J Mol Cell Biol
.
2014
Dec
;
6
(
6
):
442
57
.
[PubMed]
1674-2788
15.
Shibata
A
,
Barton
O
,
Noon
AT
,
Dahm
K
,
Deckbar
D
,
Goodarzi
AA
, et al
Role of ATM and the damage response mediator proteins 53BP1 and MDC1 in the maintenance of G(2)/M checkpoint arrest
.
Mol Cell Biol
.
2010
Jul
;
30
(
13
):
3371
83
.
[PubMed]
0270-7306
16.
Rogakou
EP
,
Boon
C
,
Redon
C
,
Bonner
WM
.
Megabase chromatin domains involved in DNA double-strand breaks in vivo
.
J Cell Biol
.
1999
Sep
;
146
(
5
):
905
16
.
[PubMed]
0021-9525
17.
Lassmann
M
,
Hänscheid
H
,
Gassen
D
,
Biko
J
,
Meineke
V
,
Reiners
C
, et al
In vivo formation of gamma-H2AX and 53BP1 DNA repair foci in blood cells after radioiodine therapy of differentiated thyroid cancer
.
J Nucl Med
.
2010
Aug
;
51
(
8
):
1318
25
.
[PubMed]
0161-5505
18.
Jiang
M
,
Zhao
L
,
Gamez
M
,
Imperiale
MJ
.
Roles of ATM and ATR-mediated DNA damage responses during lytic BK polyomavirus infection
.
PLoS Pathog
.
2012
;
8
(
8
):
e1002898
.
[PubMed]
1553-7366
19.
Spurgeon
ME
,
Cheng
J
,
Bronson
RT
,
Lambert
PF
,
DeCaprio
JA
.
Tumorigenic activity of merkel cell polyomavirus T antigens expressed in the stratified epithelium of mice
.
Cancer Res
.
2015
Mar
;
75
(
6
):
1068
79
.
[PubMed]
0008-5472
20.
Tsang
SH
,
Wang
X
,
Li
J
,
Buck
CB
,
You
J
.
Host DNA damage response factors localize to merkel cell polyomavirus DNA replication sites to support efficient viral DNA replication
.
J Virol
.
2014
Mar
;
88
(
6
):
3285
97
.
[PubMed]
0022-538X
21.
Daley
JM
,
Sung
P
.
53BP1, BRCA1, and the choice between recombination and end joining at DNA double-strand breaks
.
Mol Cell Biol
.
2014
Apr
;
34
(
8
):
1380
8
.
[PubMed]
0270-7306
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.