1. Or ph a n ides G, Rein ber g D. A u n ified t h eor y of gen e expr ession cell. Cell.
2002;108(4):439–451.
2. Millevoi S, Va gn er S. Molecu la r m ech a n ism s of eu ka r yot ic pr e-m RNA 3’ en d
pr ocessin g r egu la t ion . Nu cleic Acids Res. 2009;38(9):2757–2774.
3. Ben t ley DL. Cou plin g m RNA pr ocessin g wit h t r a n scr ipt ion in t im e a n d spa ce.
Na t Rev Gen et . 2014;15(3):163–175.
4. Xin P, Xu X, Den g C, et a l. Th e r ole of J AK/STAT sign a lin g pa t h wa y a n d it s
in h ibit or s in disea ses. In t Im m u n oph a r m a col. 2020;80:106210.
5. La ser n a , E .J ., Va ler o, M.L., Sa n z, L., et a l. P r ot eom ic a n a lysis of ph osph or yla t ed
n u clea r pr ot ein s u n der scor es n ovel r oles for r a pid a ct ion s of r et in oic a cid in t h e
r egu la t ion of m RNA splicin g a n d t r a n sla t ion . Mol E n docr in ol. 2009;23(11):17991814.
6. Ka ida D, Mot oyosh i H , Ta sh ir o E , et a l. Spliceost a t in A t a r get s SF 3b a n d in h ibit s
bot h splicin g a n d n u clea r r et en t ion of pr e-m RNA Na t . Ch em Biol. 2007;3:576–583.
7. H a sega wa M, Miu r a T, Ku zu ya K, et a l. Iden t ifica t ion of SAP 155 a s t h e Ta r get of
GE X1A (H er boxidien ea n ) An t it u m or Na t u r a l P r odu ct ACS Ch em . Biol.
2011;6:229–233.
8. Seiler M, Yosh im i A, Da r m a n R, et a l. H 3B-8800, a n or a lly a va ila ble sm a ll-m olecu le
splicin g m odu la t or, in du ces let h a lit y in spliceosom e-m u t a n t ca n cer s Na t . Med.
2018;24:497–504.
9. F u jiwa r a N, Yosh ika wa M, Ya m a za ki T, et a l. A scr een in g m et h od t u n ed for m r n a
pr ocessin g fa ct or s in h u m a n cells by eva lu a t ion of t h e lu cifer a se r epor t er a ct ivit y a n d
t h e su bcellu la r dist r ibu t ion of bu lk poly(A)+ RNA. Biosci Biot ech n ol Bioch em .
2010;74(7):1512–1516.
10. F u jit a KI, Oka m u r a M, Nish im ot o S, et a l. E st a blish m en t of a Mon it or in g Syst em
t o Det ect In h ibit ion of m RNA P r ocessin g Biosci. Biot ech n ol Bioch em .
2012;76(6):1248–1251.
11. Ku r a t a M, F u jiwa r a N, F u jit a KI, et a l. F ood-der ived com pou n ds a pigen in a n d
lu t eolin m odu la t e m r n a splicin g of in t r on s wit h wea k splice sit es.iScien ce.
2019;22:336–352.
12. Ver cellin o I, Sa za n ov LA. Th e a ssem bly, r egu la t ion a n d fu n ct ion of t h e
m it och on dr ia l r espir a t or y ch a in . Na t Rev Mol Cell Biol. 2022;23(2):141-161.
13. Ben n et t CF, La t or r e-Mu r o P, P u igser ver P. Mech a n ism s of m it och on dr ia l
r espir a t or y a da pt a t ion . Na t Rev Mol Cell Biol. 2022;23(12):817-835.
14. J eon g SY, Seol DW. Th e r ole of m it och on dr ia in a popt osis. BMB Rep. 2008;41(1):1142
22.
15. Ma r ch i S, P a t er gn a n i S, Missir oli S, et a l. Mit och on dr ia l a n d en dopla sm ic
r et icu lu m ca lciu m h om eost a sis a n d cell dea t h . Cell Ca lciu m . 2018;69:62-72.
16. E va n s RD, Gu y H I. Ma m m a lia n pyr im idin e biosyn t h esis: fr esh in sigh t s in t o a n
a n cien t pa t h wa y. J Biol Ch em . 2004;279(32):33035–33038.
17. Alcá za r-F a br a M, Na va s P, Br ea -Ca lvo G. Coen zym e Q biosyn t h esis a n d it s r ole in
t h e r espir a t or y ch a in st r u ct u r e.Bioch im ica Bioph ys Act a Bioen er g
2016;1857(8):1073–1078
18. Zh ou Y, Ta o L, Zh ou X, et a l. DH ODH a n d ca n cer : pr om isin g pr ospect s t o be
explor ed. Ca n cer Met a b. 2021;9(1):22.
19. Ya n g CF, Gopu la B, Lia n g J J , et a l. Novel AR-12 der iva t ives, P 12-23 a n d P 12-34,
in h ibit fla vivir u s r eplica t ion by blockin g h ost de n ovo pyr im idin e biosyn t h esis.
E m er g Micr obes In fect . 2018;7(1):187.
20. Lu t h r a P, Na idoo J , P iet zsch AC, et a l. In h ibit in g pyr im idin e biosyn t h esis im pa ir s
E bola vir u s r eplica t ion t h r ou gh deplet ion of n u cleoside pools a n d a ct iva t ion of
in n a t e im m u n e r espon ses.An t ivir a l Res. 2018;158: 288–302.
21. Kn igh t AD, H ejm a n owski QA, Dier ksh eide E J , et a l. In h ibit ion of h er pes sim plex
vir u s t ype 1 by t h e exper im en t a l im m u n osu ppr essive a gen t leflu n om ide
Tr a n spla n t a t ion . 2001;71:170–174.
22. F u H , Zh a n g Z, Da i Y, et a l. Br equ in a r in h ibit s en t er ovir u s r eplica t ion by t a r get in g
biosyn t h esis pa t h wa y of pyr im idin es. Am J Tr a n sl Res. 2020;12(12):8247–8255.
23. P a r k J G, Ávila -P ér ez G, Noga les A, et a l. Iden t ifica t ion a n d ch a r a ct er iza t ion of
n ovel com pou n ds wit h br oa d-spect r u m a n t ivir a l a ct ivit y a ga in st in flu en za A a n d. B
Vir u ses J Vir ol. 2020;94(7):e02149–19.
24. Lu ba n J , Sa t t ler AR, Mü h lber ger E . Th e DH ODH in h ibit or P TC299 a r r est s SARSCoV-2 r eplica t ion a n d su ppr esses in du ct ion of in fla m m a t or y cyt okin es. Vir u s Res.
2021;292:198246.
25. Xion g R, Zh a n g L, Li S. Novel a n d pot en t in h ibit or s t a r get in g DH ODH a r e br oa dspect r u m a n t ivir a ls a ga in st RNA vir u ses in clu din g n ewly-em er ged cor on a vir u s
SARS-CoV-2. P r ot ein Cell. 2020;11(10):723–739.
26. Ber ger DN, St a n ley F KT, Moor e S, et a l. ATM-depen den t pa t h wa ys of ch r om a t in
r em odellin g a n d oxida t ive DNA da m a ge r espon ses. P h ilos Tr a n s R Soc Lon d B Biol
Sci. 2017;372(1731):20160283.
27. va n Slu is M, McSt a y B. Nu cleola r r eor ga n iza t ion in r espon se t o r DNA da m a ge.
Cu r r Opin Cell Biol. 2017;46:81-86.
28. Ku r z E U, Lees-Miller SP. DNA da m a ge-in du ced a ct iva t ion of ATM a n d ATM43
depen den t sign a lin g pa t h wa ys.DNA Repa ir (Am st ). 2004;3(8–9):889–900.
29. Ta n g S, H ou Y, Zh a n g H , Tu G, Ya n g L, Su n Y, La n g L, Ta n g X, Du YE , Zh ou M, Yu
T, Xu L, Wen S, Liu C, Liu M. Oxidized ATM pr om ot es a bn or m a l pr olifer a t ion of
br ea st CAF s t h r ou gh m a in t a in in g in t r a cellu la r r edox h om eost a sis a n d a ct iva t in g
t h e P I3K-AKT, ME K-E RK, a n d Wn t -β-ca t en in sign a lin g pa t h wa ys. Cell Cycle.
2015;14(12):1908-1924.
30. Du n ph y G, F la n n er y SM, Alm in e J F, et a l. Non -ca n on ica l Act iva t ion of t h e DNA
Sen sin g Ada pt or STING by ATM a n d IF I16 Media t es NF -κB Sign a lin g a ft er
Nu clea r DNA Da m a ge. Mol Cell. 2018;71(5):745-760.e5.
31. Ilik İA, Ma lszycki M, Lü bke AK, et a l. SON a n d SRRM2 a r e essen t ia l for n u clea r
speckle for m a t ion . E life. 2020;9:e60579.
32. 文部科学省新学術領域研究『がん研究分野の特性等を踏まえた支援活動』化学療法基盤
支援活動URL: h t t p://sca ds.jfcr.or.jp/kit /kit .h t m l
33. Lydia GH , J oh n F. F la h er t y At ova qu on e: a r eview . An n P h a r m a cot h er.
1993;27(12):1488–1494
34. Br u n ea u J M, Yea CM, Spin ella -J a egle S, et a l. P u r ifica t ion of h u m a n dih ydr oor ot a t e deh ydr ogen a se a n d it s in h ibit ion by A77 1726, t h e a ct ive m et a bolit e of
leflu n om ide. Bioch em J . 1998;336(2):299–303.
35. F ox AH , Na ka ga wa S, H ir ose T, et a l. P a r a speckles: Wh er e Lon g Non codin g RNA
Meet s P h a se Sepa r a t ion . Tr en ds Bioch em Sci. 2018;43(2):124-135.
36. Meier UT. RNA m odifica t ion in Ca ja l bodies. RNA Biol. 2017;14(6):693-700.
37. Ba r dek I, Mila vec-P u r et ić V, Lipozen cić J . Aza t h iopr in e in der m a t ology. Act a
Der m a t oven er ol Cr oa t . 2007;15(4):264-8.
38. Der vieu x T, Br en n er TL, H on YY, Zh ou Y, H a n cock ML, Sa n dlu n d J T, River a GK,
Ribeir o RC, Boyet t J M, P u i CH , Rellin g MV, E va n s WE . De n ovo pu r in e syn t h esis
in h ibit ion a n d a n t ileu kem ic effect s of m er ca pt opu r in e a lon e or in com bin a t ion wit h
m et h ot r exa t e in vivo. Blood. 2002;100(4):1240-1247.
39. Robin son AD, E ich ML, Va r a m ba lly S. Dysr egu la t ion of de n ovo n u cleot ide
biosyn t h et ic pa t h wa y en zym es in ca n cer a n d t a r get in g oppor t u n it ies. Ca n cer Let t .
2020;470:134-140.
40. Dea n s MR, Mor gen s WD, Ökesli A, et a l. P a r a llel sh RNA a n d CRISP R-Ca s9 scr een s
en a ble a n t ivir a l dr u g t a r get iden t ifica t ion . Na t Ch em Biol. 2016;12(5):361–366.
41. Ar n ou ld S, Rodier G, Ma t a r G, et a l. Ch eckpoin t kin a se 1 in h ibit ion sen sit ises
t r a n sfor m ed cells t o dih ydr oor ot a t e deh ydr ogen a se in h ibit ion . On cot a r get .
2017;8(56):95206–95222.
42. La fit a -Na va r r o MC, Ven ka t eswa r a n N, Kilgor e J A, et a l. In h ibit ion of t h e de n ovo
44
pyr im idin e biosyn t h esis pa t h wa y lim it s r ibosom a l RNA t r a n scr ipt ion ca u sin g
n u cleola r st r ess in gliobla st om a cells. P LoS Gen et . 2020;16(11):e1009117.
43. H u ba ckova S, Da vidova E , Bou ka lova S, et a l. Replica t ion a n d r ibosom a l st r ess
in du ced by t a r get in g pyr im idin e syn t h esis a n d cellu la r ch eckpoin t s su ppr ess p53deficien t t u m or s. Cell Dea t h Dis. 2020;11(2):110.
44. Lu t h r a P, Na idoo J , P iet zsch AC, et a l. In h ibit in g pyr im idin e biosyn t h esis im pa ir s
E bola vir u s r eplica t ion t h r ou gh deplet ion of n u cleoside pools a n d a ct iva t ion of
in n a t e im m u n e r espon ses.An t ivir a l Res. 2018;158: 288–302.
45. An a st a sia AK, Vla dim ir VR, Bor is VC, et a l. P yr im idin e biosyn t h esis lin ks
m it och on dr ia l r espir a t ion t o t h e p53 pa t h wa y. P r oc Na t l Aca d Sci U S A.
2010;107(29):12828–12833.
46. Ra in ey MD, Ch a r lt on ME , St a n t on RV, et a l. Tr a n sien t in h ibit ion of ATM kin a se is
su fficien t t o en h a n ce cellu la r sen sit ivit y t o ion izin g r a dia t ion . Ca n cer Res.
2008;68(18):7466–7474.
47. Ta n a ka T, H a licka H D, Tr a ga n os F, et a l. In du ct ion of ATM a ct iva t ion , h ist on e
H 2AX ph osph or yla t ion a n d a popt osis by et oposide: r ela t ion t o cell cycle ph a se. Cell
Cycle. 2007;6(3):371-376.
48. Zh a n g A, Lyu YL, Lin CP, et a l. A pr ot ea se pa t h wa y for t h e r epa ir of t opoisom er a se
II-DNA cova len t com plexes. J Biol Ch em . 2006;281(47):35997–36003.
49. Sh a r m a A, Sin gh K, Alm a sa n A. H ist on e H 2AX ph osph or yla t ion : a m a r ker for DNA
da m a ge Met h ods. Mol Biol. 2012;920:613–626.
50. Sa n t or iello C, Spor r ij A, Ya n g S, et a l. RNA h elica se DDX21 m edia t es n u cleot ide
st r ess r espon ses in n eu r a l cr est a n d m ela n om a cells. Na t Cell Biol.
2020;22(4):372–379.
51. Gr za n ka M, P iekiełko-Wit kowska A. Th e Role of TCOF 1 Gen e in H ea lt h a n d
Disea se. In t J Mol Sci. 2021;22(5):2482.
52. Kor sh olm LM, Gá l Z, Lin L, et a l. Dou ble-st r a n d br ea ks in r ibosom a l RNA gen es
a ct iva t e a dist in ct sign a lin g a n d ch r om a t in r espon se t o fa cilit a t e n u cleola r
r est r u ct u r in g a n d r epa ir. Nu cleic Acids Res. 2019;47(15):8019–8035.
53. Ca lo E , Gu B, Bowen ME , et a l. Tissu e-select ive effect s of n u cleola r st r ess a n d
r DNA da m a ge in developm en t a l disor der s. Na t u r e. 2018;554(7690):112–117.
54. In ou e A, Tsu ga wa K, Toku n a ga K, et a l. S1-1 n u clea r dom a in s: ch a r a ct er iza t ion
a n d dyn a m ics a s a fu n ct ion of t r a n scr ipt ion a l a ct ivit y. Biol Cell.
2008;100(9):523–535.
55. Ch a t h a m J C, You n g ME , Zh a n g J . Role of O-lin ked N-a cet ylglu cosa m in e (O-GlcNAc)
m odifica t ion of pr ot ein s in dia bet ic ca r diova scu la r com plica t ion s. Cu r r Opin
45
P h a r m a col. 2021;57:1–12.
56. Ben n et t E P, Ma n del U, Cla u sen H , et a l. Con t r ol of m u cin -t ype O-glycosyla t ion : a
cla ssifica t ion of t h e polypept ide Ga lNAc-t r a n sfer a se gen e fa m ily. Glycobiology.
2012;22(6):736–756.
57. Ch en J , Ya n g S. Ca t a lyt ic m ech a n ism of UDP -glu cose deh ydr ogen a se. Bioch em Soc
Tr a n s. 2019;47(3):945–955.
58. Lewis BA, Bu r lin ga m e AL, Myer s SA. H u m a n RNA P olym er a se II P r om ot er
Recr u it m en t in Vit r o Is Regu la t ed by O-Lin ked N-Acet ylglu cosa m in ylt r a n sfer a se
(OGT). J Biol Ch em . 2016;291(27):14056–14061.
59. E ch izen ya S, Ish ii Y, Kit a za wa S, et a l. Discover y of a n ew pyr im idin e syn t h esis
in h ibit or er a dica t in g gliobla st om a -in it ia t in g cells. Neu r o On col. 2020;22(2):229–239.
60. Ma da k J T, Ba n kh ea d A 3r d, Cu t h ber t son CR, et a l. Revisit in g t h e r ole of
dih ydr oor ot a t e deh ydr ogen a se a s a t h er a peu t ic t a r get for ca n cer. P h a r m a col Th er.
2019;195:111–131.
61. Zh ou Y, Ta o L, Zh ou X, et a l. DH ODH a n d ca n cer : pr om isin g pr ospect s t o be
explor ed. Ca n cer Met a b. 2021;9(1):22.
62. Ba r-Or A, P a ch n er A, Men gu y-Va ch er on F, et a l. Ter iflu n om ide a n d it s m ech a n ism
of a ct ion in m u lt iple scler osis. Dr u gs. 2014;74(6):659–674.
63. Ala m r i RD, E lm eligy MA, Alba la wi GA, et a l. Leflu n om ide a n im m u n om odu la t or
wit h a n t in eopla st ic a n d a n t ivir a l pot en t ia ls bu t dr u g-in du ced liver in ju r y: a
com pr eh en sive r eview. In t Im m u n oph a r m a col. 2021;93:107398.
64. Lolli ML, Sa in a s S, P ippion e AC, et a l. Use of h u m a n dih ydr oor ot a t e deh ydr ogen a se
(h DH ODH ) in h ibit or s in a u t oim m u n e disea ses a n d n ew per spect ives in ca n cer
t h er a py. Recen t P a t An t ica n cer Dr u g Discov. 2018;13:86–105.
65. Sa in a s S, P ippion e AC, Lu pin o E , et a l. Ta r get in g m yeloid differ en t ia t ion u sin g
pot en t 2-h ydr oxypyr a zolo [1,5- a ]pyr idin e sca ffold-ba sed h u m a n dih ydr oor ot a t e
deh ydr ogen a se in h ibit or s. J Med Ch em . 2018;61(14):6034–6055.
66. Mu eh ler A, Koh lh of H , Gr oeppel M, et a l. Sa fet y, Toler a bilit y a n d P h a r m a cokin et ics
of Vidoflu dim u s ca lciu m (IMU-838) Aft er Sin gle a n d Mu lt iple Ascen din g Or a l Doses
in H ea lt h y Ma le Su bject s. E u r J Dr u g Met a b P h a r m a cokin et . 2020;45(5):557-573.
67. Wa n g X, Ya n g K, Wu Q, et a l. Ta r get in g pyr im idin e syn t h esis a ccen t u a t es
m olecu la r t h er a py r espon se in gliobla st om a st em cells. Sci Tr a n sl Med.
2019;11:1–15.
46
8. 謝辞
本研究にあたり、多くの方々にご協力を賜りました。まずは勝手ばかりで未熟な私を肯定
し、日々ご指導くださいました、指導教官の近畿大学農学部教授 増田誠司博士に心からの御
礼を申し上げます。本研究の機会を与えてくださり、申請に際し適切なご助言を賜りまし
た、京都大学大学院生命科学研究科教授 片山高嶺博士に深く御礼申し上げます。京都大学大
学院生命科学研究科特定准教授 阪中幹祥博士、同助教 加藤紀彦博士には、研究室での活動
にあたって陰に陽に渡り手助けをしていただきました、深く感謝いたします。京都大学大学
院生命科学研究科教授 永尾雅哉博士、准教授 神戸大朋博士には折に触れてご助言を賜り、
見守っていただきました、厚く御礼申し上げます。京都大学大学院生命科学研究科助教 西野
勝俊博士には解析にあたってご指導とご助言を賜りお世話になりました、深く御礼申し上
げます。
本研究の実験を行うにあたり、様々な方にご助力いただきました。NE AT1の解析用プラ
スミドを提供いただきました大阪大学大学院生命機能研究科教授
廣瀬哲郎博士、抗
n u cleolin 抗体をご提供いただきました京都大学大学院生命科学研究科准教授
吉村成弘博
士、抗NE AT1プローブを作出していただきました藤原奈央子氏に心より御礼申し上げま
す。
本研究に際し、日ごろからご協力と有意義な議論をしてくださいました、京都大学大学
院生命科学研究科分子応答機構学の皆さま、そして生体情報応答学の皆さまに深く感謝し
たします。研究室での様々な事務を行っていただきました、事務補佐員 清水久美子氏と嶋
林かほる氏に厚く御礼申し上げます。研究室で出会った上記皆さまには研究へのご助力だ
けでなく、大学院での生活全般に渡って大変お世話になりました。心より御礼申し上げま
す。
大学院に通い続けるために、研究活動以外でも多くの方々のご助力を賜りました。この
5年間で出会ったすべての方々に感謝申し上げます。
最後に、多くの心配をかけてしまいましたが、研究活動を続けていくことを暖かく見守
ってくださった家族に心より感謝申し上げます。
令和4年12月
三宅俊太郎
47
本論文は以下の学術論文の内容に基づいて書かれたものである。
Miya ke S, Ma su da S.
In h ibit ion of m it och on dr ia l com plex III or dih ydr oor ot a t e deh ydr ogen a se (DH ODH )
t r igger s for m a t ion of poly(A)+ RNA foci a dja cen t t o n u clea r speckles followin g
a ct iva t ion of ATM (a t a xia t ela n giect a sia m u t a t ed).
RNA Biol. 2022;19(1):1244-1255. doi: 10.1080/15476286.2022.2146919.
48
...