Skipper Ben Hunt is the most notable omission after suffering a fractured fibula, initially diagnosed as a cork, in last week's big win over Manly.
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Hunt courageously played on, but will miss at least a month with the injury in a big blow on the team and personal front given the rich vein of form in which he started the season.
Clune partnered Hunt in a round one defeat to Cronulla in the absence of Corey Norman who was serving a one-game suspension. He'll now partner Norman, while Wiliame will start in the centres in place of Jack Bird who plead guilty to a contrary conduct charge and will miss a week.
Jackson Ford comes into the 17 in place of Wiliame, who's come off the bench in his side's opening three games, while Andrew McCullough will skipper the side in Hunt's absence in just his fourth game for the club.
It's a frustrating development for Bird after two years in the injury wilderness, while Hunt was also nudging top form under Griffin.
Centre Zac Lomax is confident Hunt will bounce back on his return, saying his courage in playing on against the Sea Eagles shows why he was the right man to replace Cam McInnes as captain.
"I'm really disappointed for him, he's copped a fair bit of stick throughout his years here at the Dragons, but he just absolutely typifies what a captain is," Lomax said.
"There's a lot of people in the team that could have been a captain, I think that's the same for most teams, but he's the right leader for our club. He's such a selfless person, he loves the boys to bits and he goes out there every game putting his body on the line and it shows.
"[Last week] was another example, it comes back and he had a fracture in his leg and he was still out there trying to put in a good performance for the team.
"That's just the way he is and they way he's always been. He'll be gutted after a good couple of wins, but if there's anyone who can bounce back from it it's Benny."
The disruptions are untimely for a side just finding its groove but Lomax, who grabbed a double against the Sea Eagles, says it hasn't put a dent in confidence ahead of Sunday's trip to Newcastle.
"The team's feeling really good," Lomax said.
"As any team would tell you, it's always a better few days at training after a win. It was good to run away with it there at the end. Everyone's just working for each other on and off the ball so, if we keep doing that, it'll go a long way to putting us in the fight in most games.
"Hook's just stripped it all right back and has been very clear with what he wants from us as players. He's instilled a lot of confidence in all of us which is good, but it's only early days."
Dragons team for round four:
- Matt Duft
- Cody Ramsey
- Brayden Wiliame
- Zac Lomax
- Mikaele Ravalaw
- Corey Norman
- Adam Clune
- Blake Lawrie
- Andrew McCullough (c)
- Paul Vaughan
- Josh Kerr
- Tariq Sims
- Tyrell Fuimaono
- Poasa Faamausili
- Trent Merrin
- Daniel Alvaro
- Jackson Ford