Work and Pensions Secretary Amber Rudd has quit the cabinet and the Conservatives, dealing a fresh setback to Boris Johnson's government.
Ms Rudd hit out at the prime minister over his decision to kick out 21 Tory MPs and ban them from standing for the party at a general election – attacking the move as an "act of political vandalism".
The rebels had the Tory whip removed after they voted last Tuesday with the Opposition in their attempts to stop the UK leaving the European Union without a deal on 31 October.
Ms Rudd, who was seen as a leading pro-European voice in the government, wrote: "I cannot stand by as good, loyal moderate Conservatives are expelled."
She said in her resignation letter: "This short-sighted culling of my colleagues has stripped the party of broad-minded and dedicated Conservative MPs.
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"I cannot support this act of political vandalism."
She called it an "assault on decency and democracy" after the prime minister sacked 21 "talented, loyal One Nation Conservatives".
More from Amber Rudd
And she also said she thought a no-deal Brexit was now the government's key aim.
While she had accepted the need to keep no-deal as an option, the now Independent MP said she "no longer believed leaving with a deal is the government's main objective".
The 21 rebels voted to give Opposition MPs control of the order paper and start the process of blocking a no-deal.
They included two former chancellors Philip Hammond and Ken Clarke as well as Sir Winston Churchill's grandson Sir Nicholas Soames.
I have resigned from Cabinet and surrendered the Conservative Whip.
I cannot stand by as good, loyal moderate Conservatives are expelled.
I have spoken to the PM and my Association Chairman to explain.
I remain committed to the One Nation values that drew me into politics. pic.twitter.com/kYmZHbLMES
— Amber Rudd MP (@AmberRuddHR) September 7, 2019
On Twitter, Hastings and Rye MP Ms Rudd, who was also minister for women and equalities, said: "I have resigned from cabinet and surrendered the Conservative whip.
"I have spoken to the PM and my association chairman to explain.
"I remain committed to the One Nation values that drew me into politics."
A No 10 spokesperson reacted by saying: "We are disappointed to learn that Amber has chosen to leave government and the party.
"She was a talented welfare minister but all ministers who joined the cabinet signed up to leaving the EU on 31 October come what may, delivering on the referendum result as the public were promised. That has not changed."
A senior government source said: "As the polls show, the public do not back attempts by some MPs to cancel the referendum.
"Resignations to chase headlines won't change the fact that people want Brexit done so that government can deliver on the domestic priorities people care about like more police, new hospitals and great schools."
Meanwhile, Health Secretary Matt Hancock tweeted: "So sorry to see Amber resign – a first-rate minister, genuinely wonderful person, and someone I'm proud to call my friend.
"The Conservative Party has always been a broad church shaped by those within it. Gutted to see Amber leave – but hope other One Nation Tories will stay and fight for the values we share."
David Gauke, the former secretary of state for justice and lord chancellor who was among the 21 rebels, tweeted: "I'm sure this has not been an easy decision. But it is brave and principled and is all about putting the national interest first."
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